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A California-sponsored, 18-month, tobacco-free intervention in residential substance use disorder (SUD) programs was associated with increases in tobacco-free grounds and tobacco-related client services. The current study examined whether positive results would be replicated in 11 programs participating subsequently. Program directors ( N  = 11) completed surveys of tobacco-related policies pre- and post-intervention. Pre- ( n  = 163) and post-intervention ( n  = 128) cross-sectional staff surveys examined tobacco-related training, beliefs, practices, smoking policy, and smoking status. Directors reported increases in tobacco-free grounds (from 3 to 8 programs), tobacco-related staff training (1 to 10 programs), tobacco cessation staff services (1 to 9 programs) and nicotine replacement therapy (NRT) provision (6 to 10 programs). At post-intervention, staff were more likely to report smoke-free workplaces ( p  = 0.008), positive beliefs about treating tobacco use ( p  = 0.017) and less likely to report current smoking ( p  = 0.003). Clinical staff were more likely to report tobacco-related training receipt ( p  = 0.001), program-level NRT provision ( p  = 0.009) and conducting tobacco-related client services ( p  < 0.0001) post-intervention. Findings of increases in tobacco-free grounds and tobacco cessation client services corroborated prior results. These and the additional finding of decreases in staff smoking strengthen evidence that initiatives supporting tobacco-free policies can be successfully implemented in SUD treatment.

Introduction: Polycystic ovary syndrome (PCOS) seems to be associated with increased ovarian sympathetic nerve activity and in rodent models of PCOS reducing the sympathetic drive to the ovary, through denervation or neuromodulation, improves ovulation rate. We hypothesised that sympathetic nerves work with gonadotropins to promote development and survival of small antral follicles to develop a polycystic ovary phenotype., Methods: Using a clinically realistic ovine model we showed a rich sympathetic innervation to the normal ovary and reinnervation after ovarian transplantation. Using needlepoint diathermy to the nerve plexus in the ovarian vascular pedicle we were able to denervate the ovary resulting in reduced intraovarian noradrenaline and tyrosine hydroxylase immunostained sympathetic nerves. We developed an acute polycystic ovary (PCO) model using gonadotrophin releasing hormone (GnRH) agonist followed infusion of follicle stimulating hormone (FSH) with increased pulsatile luteinising hormone (LH). This resulted in increased numbers of smaller antral follicles in the ovary when compared to FSH infusion suggesting a polycystic ovary., Results: Denervation had no effect of the survival or numbers of follicles in the acute PCO model and did not impact on ovulation, follicular and luteal hormone profiles in a normal cycle., Discussion: Although the ovary is richly inervated we did not find evidence for a role of sympathetic nerves in ovarian function or small follicle growth and survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Duncan, Nicol, O’Hare, Witherington, Miranda, Campbell, Thomas and Rae.)

Tobacco-related morbidity and mortality disproportionately affect people with substance use disorders (SUD). Encouraging overall wellness may support tobacco use cessation. We investigated relationships between wellness (health status, physical activity, sugar-sweetened beverage (SSB) consumption), cigarette smoking, and smoking cessation among SUD treatment patients to inform clinical care. Cross-sectional surveys were conducted with 395 patients in 20 California residential SUD programs. Using multivariate regression, we examined associations between smoking status and wellness. Among smokers, we examined associations between lifetime smoking exposure, cessation behaviors and attitudes, and wellness. Compared to nonsmokers (n = 121), smokers (n = 274) reported more SSB consumption, poorer physical health, and more respiratory symptoms. Among smokers, SSB consumption and respiratory symptoms increased per ten pack-years of smoking. Smokers with respiratory symptoms reported higher motivation to quit and more use of nicotine replacement therapy (NRT). Smokers with more days of poor mental health reported lower motivation to quit. Overall, cigarette smoking was associated with other health-risk behaviors among SUD treatment patients. Respiratory symptoms may increase, and poor mental health may decrease, SUD patients' intent to quit smoking. To reduce chronic disease risk among SUD patients, treatment programs should consider promoting overall wellness concurrently with smoking cessation.

Background: Smoking prevalence is high among people in substance use disorder (SUD) treatment, and program interventions to address smoking are often complex and lengthy. This cluster-randomized trial tested whether a brief multi-component intervention impacted tobacco outcomes among staff and clients., Methods: Seven SUD treatment programs were randomly assigned to the multi-component intervention or to waitlist control. The 6-month intervention included a leadership motivation assessment, program incentives, 4 staff training sessions and a leadership learning community session. Survey data were collected from staff and clients at pre- and post-intervention. Outcomes were first compared across condition (intervention vs waitlist control), and then examined pre- to post-intervention with condition collapsed., Results: Staff in the intervention (n = 48) and control conditions (n = 26) did not differ at post-intervention on smoking prevalence, self-efficacy to help clients quit, or practices used to help clients quit smoking. Intervention clients (n = 113) did not differ from controls (n = 61) in smoking prevalence or receipt of tobacco services. Pre-post comparisons collapsed across condition showed a decrease in client and staff smoking prevalence, which could not be attributed to the intervention, and a decrease in client receipt of cessation medication., Conclusion: The brief multi-component intervention did not support changes in smoking prevalence or in tobacco-related services received by clients. Other intervention features are needed to reduce smoking among SUD clients., Trial Registration: Randomization occurred at the program level and outcomes measured are program-level measures. Accordingly, the trial is not registered., (© 2023. The Author(s).)

Introduction: Interest in wellness interventions in substance use disorder (SUD) treatment is growing although evidence remains limited. This study evaluated nutrition, physical activity, nutrition and physical activity counseling, and relationships of counseling with wellness behavior before and after a wellness-oriented, tobacco-free policy intervention in 17 residential SUD programs., Methods: Clients completed cross-sectional surveys reporting sugar-sweetened beverage consumption, physical activity, and receipt of nutrition and physical activity counseling before (n= 434) and after (n = 422) an 18-month intervention. Multivariable regression models assessed pre-post-intervention differences in these variables and examined associations of nutrition counseling with sugar-sweetened beverage consumption and physical activity counseling with physical activity., Results: Post-intervention clients were 83% more likely than pre-intervention clients to report nutrition counseling (p = 0.024). There were no pre-post- differences for other variables. Past week sugar-sweetened beverage consumption was 22% lower among clients reporting nutrition counseling than for those who did not (p = 0.008) and this association did not vary by time (pre/post). There was a significant interaction of physical activity counseling receipt by time on past week physical activity (p = 0.008). Pre-intervention clients reporting physical activity counseling had 22% higher physical activity than those who did not; post-intervention clients reporting physical activity counseling had 47% higher physical activity., Conclusion: A wellness policy intervention was associated with increased nutrition counseling. Nutrition counseling predicted lower sugar-sweetened beverage consumption. Physical activity counseling predicted higher physical activity, an association that was greater post-intervention. Adding wellness components to tobacco-related interventions may promote health among SUD clients., Competing Interests: None., (© 2023 The Authors. Published by Elsevier B.V.)

Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain.

Background: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting., Methods: We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing., Results: Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation., Conclusions: Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Implementing tobacco-free policies in substance use disorders (SUD) treatment may reduce tobacco-related, health disparities. This study examined adoption of tobacco-related policy and practices in six residential programs participating in a California-sponsored, 18-month, tobacco-free policy intervention., Methods: Directors (N=6) completed surveys of tobacco-related policies before and after the intervention. Staff completed cross-sectional surveys assessing tobacco-related training, beliefs, practices, workplace smoking policy, tobacco cessation program services, and smoking status pre- (n=135) and post-intervention (n=144)., Results: Director surveys indicated no programs had tobacco-free grounds, one provided tobacco-related staff training, and two provided nicotine replacement therapy (NRT) pre-intervention. At post-intervention, 5 programs had implemented tobacco-free grounds, 6 provided tobacco cessation training, and 3 provided NRT. Across all programs, staff were more likely to report smoke-free workplaces (AOR = 5.76, 95% CI1.14,29.18) post- versus pre-intervention. Staff positive beliefs towards addressing tobacco use were higher post-intervention (p<0.001). Odds of clinical staff reporting tobacco-related training participation (AOR = 19.63, 95% CI14.21,27.13) and program-level provision of NRT (AOR = 4.01, 95% CI 1.54, 10.43) increased post- versus pre-intervention. Clinical staff reporting they provided tobacco cessation services were also higher post-intervention (p= 0.045). There were no changes in smoking prevalence or quit intention among smoking staff., Conclusion: A tobacco-free policy intervention in SUD treatment was associated with implementation of tobacco-free grounds, tobacco-related training among staff, more positive staff beliefs towards and delivery of tobacco cessation services to clients. The model may be improved with greater emphasis on staff policy awareness, facilitating availability of NRT, and reducing staff smoking., Competing Interests: The authors state that they have no conflicts of interest., (© 2022 The Authors. Published by Elsevier B.V.)

Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely in minimising the primary tumour, and eliminating any undetected micro metastases. Trials of neoadjuvant androgen deprivation therapy aim to address these challenges. Patients typically respond well to neoadjuvant treatment, showing regression of the primary tumour and negative surgical margins at the time of resection, however the majority of patients relapse and progress to metastatic disease. The mechanisms affording this resistance are largely unknown. This commentary attempts to explore theories of resistance more broadly, namely, clonal evolution, cancer stem cells, cell persistence, and drug tolerance. Moreover, it aims to explore the application of these theories in the PCa setting. This commentary also highlights the distinction between castration resistant PCa, and neoadjuvant resistant disease, and identifies the markers and characteristics of neoadjuvant resistant disease presented by current literature.

Background: Co-use of tobacco and cannabis has been associated with greater dependence on and lower quit rates for both substances. Tobacco/cannabis co-use among individuals with substance use disorders (SUDs), a population with high rates of cigarette smoking, may hinder the effectiveness of smoking cessation interventions. We examined rates of lifetime (i.e., ever vs. never) cannabis use among current cigarette smokers in SUD treatment, and we identified the subgroup who had used tobacco and cannabis together in the form of blunts and/or spliffs. We then examined variables associated with lifetime use of blunts and/or spliffs., Methods: We surveyed 562 clients in 20 residential SUD treatment programs in California, USA, in 2019. Measures included demographics, lifetime use of any cannabis product, lifetime use of blunt/spliffs, patterns of tobacco use, and smoking cessation-related questions. We asked current cigarette smokers who also reported lifetime cannabis use whether they had ever used blunts and/or spliffs. We then assessed relationships of demographic, tobacco use, use of cannabis/tetrahydrocannabinol (THC) in e-cigarettes/vape pens, and smoking cessation-related variables with ever use versus never use of blunts/spliffs., Results: Among 340 current cigarette smokers, 93.2% (n = 317) reported lifetime use of any cannabis product. Among current cigarette smokers with lifetime cannabis use, 64.4% reported lifetime blunt/spliff use. Compared to those who had never used blunts/spliffs, lifetime blunt/spliff users were more likely to be younger (OR = 0.93, 95% CI 0.90-0.95), more likely to report lifetime use of cigars/cigarillos (OR = 2.95, CI 1.37-6.32), and to have ever used cannabis/THC in e-cigarettes/vape pens (OR = 4.26, CI 1.54-11.80). They were less often ready to quit smoking within 30 days (OR = 0.37, CI 0.23-0.60), but more likely to want help with smoking cessation (OR = 2.39, CI 1.52-3.77)., Conclusion: Current cigarette smokers in SUD treatment reported a high prevalence of lifetime cannabis use. Smokers with a history of blunt/spliff use were more likely to report lifetime use of e-cigarettes/vape pens for cannabis/THC delivery. They wanted help to quit smoking, but felt less prepared to quit in the next 30 days. Cannabis co-use may warrant clinicians' attention when providing smoking cessation interventions during SUD treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Natriuretic peptides (NPs) have been reported to have critical roles in follicular development and oocyte maturation in rodents. This study aimed to extend our current understanding of NP-mediated signalling pathways and mechanisms of action in the follicles of a monovulatory species. Ovine granulosa cells (GCs) and theca cells (TCs) were cultured under conditions designed to allow gonadotrophin-stimulated cell differentiation. Gene expression analysis was performed by qualitative (q)PCR for NPs and NPRs (between 16 and 96 h of culture) and VEGF120 and VEGF164 (between 16 and 144 h of culture). A qualitative analysis of the production of NP/NPR family members and NP ligand/receptor associations was carried out utilising a highly sensitive immunological approach known as 'proximity ligation assay' (PLA). All NPRs were observed in GCs, while NPRA was absent in TCs. In GCs, gene expression of NPRA, NPRB and NPRC was apparent but only active BNP and CNP and not ANP, were detected. Also in GCs, ANP but not CNP was able to significantly (P < 0.05) reduce oestradiol and increase (P < 0.05) progesterone. Inhibition of VEGF164 by ANP and CNP (P < 0.01) after 48 h of culture preceded up-regulation of VEGF120 by ANP (P < 0.01) after 144 h, but not CNP. Taken together, these findings appear to demonstrate that NP responsiveness in the GC compartment of sheep follicles is multi-facilitated, utilising both autocrine and paracrine stimulation pathways.

The aim was to define the pattern and physiological concentrations of FSH and LH required for the selection of a single dominant follicle in mono-ovulatory species. A series of five experiments was carried out using gonadotrophin-releasing hormone agonist-induced hypogonadal heifers. Animals were infused with different patterns of either FSH and/or LH followed by an ovulatory dose of human chorionic gonadotrophin. Follicular response was monitored by ultrasound scanning and blood samples were collected to measure concentrations of FSH, LH, oestradiol and progesterone. The main findings were: (1) physiological concentrations of FSH given as a continuous infusion and for an adequate duration, in the presence of basal LH, with or without LH pulses, are capable of inducing a superovulatory response, (2) initial exposure to FSH followed by LH pulses alone stimulate the development of multiple preovulatory follicles, confirming that ovarian follicles are capable of transferring dependence on gonadotrophins from FSH to LH, (3) while LH pulses appear not to have a major effect on the pattern of preovulatory follicle development, adequate LH pulsatile support is required for full oestradiol synthesis and (4) the duration of initial exposure to FSH and the ability to transfer the dependence from FSH to LH are critical for the selection of a single dominant follicle. In conclusion, this experimental series confirms that the duration of initial exposure to FSH and the ability of the selected follicle to transfer its gonadotrophic dependence from FSH to LH are critical for the selection of a single dominant follicle in cattle.

Introduction: We examined rates of use, health risk perceptions and reasons for use of combustible and non-combustible tobacco products among clients enrolled in addictions treatment across the United States., Methods: Participants (N = 1153) completed tobacco use surveys and rated health risk perception of all products. Users of non-cigarette products reported their main reason for use of each product. Logistic regression analyses examined associations between health risk perceptions and product use, including combustible cigarette use, and between reasons for use and non-cigarette product use., Results: Cigarette smoking was reported by 77.5%, followed by use of e-cigarettes (26.6%), little filtered cigars (LFCs)/cigarillos (15.4%), smokeless tobacco (11.4%), and cigars (8.4%). Lower perceived health risk of cigarettes was associated with smoking cigarettes (OR = 0.985, 95% CI: 0.975-0.995, p = 0.005). Lower perceived health risk of e-cigarettes was associated with e-cigarette use (OR = 0.991, 95% CI: 0.984-0.998, p = 0.023). Users of cigars and users of LFC/cigarillos (versus other product use) were more likely to report their main reason for use as "enjoying flavor/ taste", and smokeless tobacco users were more likely to report "at times when can't smoke" as their main reason for use compared with other reasons. E-cigarette users were more likely to report to "reduce/quit cigarettes" as their main reason for use as compared to all other reasons except "reduce health risk"., Conclusion: Treating smoking in addictions treatment should assess all tobacco product use, accuracy of health risk perceptions, and use of e-cigarettes to reduce/quit smoking, in order to promote cessation of combustible tobacco., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ovarian cortical tissue cryopreservation is a relatively novel approach to preserving fertility in women diagnosed with cancer. However, the effects of freezing-thawing are not fully understood, mainly due to the lack of suitable methods to assess tissue's survival after thawing. Disparities in steroid production have been associated with ovarian failure by disrupting folliculogenesis, ovulation and oocyte apoptosis. Moreover, specific microRNAs, identified in human ovarian follicles, are thought to play a fundamental role in folliculogenesis. In this study, we investigated the possible interplay between the ovarian steroidal production and microRNA expression patterns in spent culture media, as potential non-invasive markers for ovarian tissue damage after cryopreservation. Cryopreservation of ovarian cortical tissue decreased (P<0.05) both steroid production (oestradiol and progesterone) and expression of microRNA-193b and 320A in spent culture media over 5 days, however, expression of microRNA-24 increased (P<0.05). The number of primordial follicles were also reduced (P<0.05) in fresh-cultured and cryopreserved-cultured cortical tissues when compared with fresh tissues. Downregulation of microRNA-193b and microRNA-320A together with upregulation of microRNA-24 could have a synergistic role in cell apoptosis, and consequently leading to reduced oestradiol and progesterone production. Thus, there appears to be an interplay between these microRNAs, ovarian steroid production and cell damage, which can be further explored as novel non-invasive markers of cell damage following cryopreservation.

Objectives: Research on sex differences in responses to cigarette graphic warning labels (GWLs) has been limited despite tobacco-related, health disparities for women. We examined whether women had stronger responses to certain labels than to others, whether this pattern differed from men's, and whether there were overall sex ratings differences., Methods: Smokers (N = 881) in 24, addictions treatment programs rated 3 of 9 Food and Drug Administration-developed labels on credibility, message reactance, quit motivation, and negative emotions. Participants rated one label depicting a woman and/or baby, and 2 depicting tobacco-related disease or male images., Results: Women's (n = 432) ratings of labels depicting women/babies versus other labels did not differ from men's (n = 449) ratings. Women had higher ratings than men across all labels combined on credibility (p < .001), quit motivation (p = .007), and negative emotions (p < .001). Individual labels were analyzed for sex differences. Women's ratings were higher on credibility for 3 of 9 labels, and on negative emotions for 7 of 9 labels., Conclusions: Female smokers in addictions treatment had generally stronger responses to GWLs than men, supporting GWL implementation in the United States to help close the sex gap in smoking cessation., Competing Interests: Conflict of Interest Statement All authors of this article declare they have no conflicts of interest.

There are higher rates of menthol cigarette smoking within certain population subgroups. Limited research has examined menthol use among individuals in treatment for substance use disorders (SUD), a population with a high prevalence of cigarette smoking, poor smoking cessation outcomes, and high tobacco disease burden. Survey data were collected from 863 smokers sampled from 24 SUD treatment programs affiliated with the NIDA Clinical Trials Network (CTN) in the United States. Prevalence of menthol cigarette smoking was examined for the sample. Bivariate and multivariate analyses were used to examine demographic and tobacco use characteristics associated with menthol cigarette smoking. Overall, the prevalence of menthol smoking among individuals in SUD treatment was 53.3%. Smoking menthol versus non-menthol cigarettes was associated with being female (AOR=1.61, p=0.003), African American (AOR=7.89, p<0.001), Hispanic/Latino (AOR=3.39, p<0.001), and lower odds of having a college degree (AOR=0.49, p=0.015). Controlling for demographic factors, menthol smokers were more likely to report marijuana (AOR=3.33, p<0.007) as their primary drug compared to alcohol. Lastly, menthol smokers were more likely to report interest in getting help for quitting smoking (AOR=1.53, p=0.01), although they were not more likely to report making a past year quit attempt. In conclusion, use of menthol cigarettes was higher among smokers in SUD treatment than in general population smokers. Regulatory policies targeting the manufacture, marketing, or sale of menthol cigarettes may benefit vulnerable populations, including smokers in SUD treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It has been suggested that first embryo cleavage can be related with the embryonic-abembryonic axis at blastocyst stage in mice. Thus, cells of the 2-cell embryo might be already biased to form the inner cell mass or trophectoderm. This study was conducted to observe the possible effects of embryo biopsy on cell allocation patterns during embryo preimplantation in two different mouse strains and the effects of these patterns on further development. First, one blastomere of the 2-cell embryo was injected with a lipophilic tracer and cell allocation patterns were observed at blastocyst stage. Blastocysts were classified into orthogonal, deviant or random pattern. For the first experiment, embryos were biopsied at 8-cell stage and total cell counts (TCC) were annotated. Furthermore, non-biopsied blastocysts were transferred into foster mothers. Then, pups and their organs were weighed two weeks after birth. Random pattern was significantly recurrent (≈60%), against orthogonal (<22%) and deviant (<22%) patterns among groups. These patterns were not affected by biopsy procedure. However, TCC on deviant embryos were reduced after biopsy. Moreover, no differences were found between patterns for implantation rates, litter size, live offspring and organ weights (lungs, liver, pancreas and spleen). However, deviant pups presented heavier hearts and orthogonal pups presented lighter kidneys among the group. In conclusion, these results suggest that single blastomere removal does not disturb cell allocation patterns during pre-implantation. Nonetheless, the results suggest that embryos following different cell allocation patterns present different coping mechanisms against in vitro manipulations and further development might be altered., (© 2017 Society for Reproduction and Fertility.)

Although individuals in substance use disorders (SUD) treatment continue to smoke at high rates, regulatory, policy and programming changes promoting tobacco cessation are being implemented and some patients quit successfully. We examined associations of smoking patterns, tobacco advertising receptivity, anti-tobacco message awareness, health risk perception, attitudes towards addressing smoking and availability of smoking cessation services with quitting smoking during SUD treatment. Surveys were completed by 1127 patients in 24 programs chosen randomly, stratified by program type (residential, methadone maintenance, outpatient), from among publicly funded, adult treatment programs within the National Drug Abuse Treatment Clinical Trials Network. Among respondents who had been in SUD treatment for at least one month, there were 631 current smokers and 52 former smokers who reported quitting smoking during treatment for at least one month prior to survey completion; these respondents comprised our sample (N=683). Results showed that participants who reported health concerns as a reason for quitting were 1.27 times more likely to have quit during treatment (p=0.015) than those reporting health concerns affected quitting a little or not at all. Additionally, participants who reported that smoking cessation was part of their personal treatment plan during SUD treatment were 1.08 times more likely to have quit during treatment (p<0.001). Participants in methadone treatment were 49% less likely to report successfully quitting during treatment than those in outpatient treatment (95%CI: 0. 35-0.75, p<0.001). Leveraging health concerns about smoking and including smoking cessation in an individualized treatment plan may help increase smoking cessation during SUD treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Temporomandibular joint disorder (TMD) is a complex musculoskeletal disorder that presents with pain, limited jaw opening, and abnormal noises in the temporomandibular joint. Despite the significant impact that TMD has in terms of suffering and financial burden, relatively few new treatments have emerged; therefore, development of novel treatments to treat TMD pain remains a high priority. The rationale of this study was to use a double-blind, vehicle-controlled clinical trial to evaluate the effects of a high-concentration (8%) capsaicin cream on TMD. This is based on the hypothesis that targeting TRP vanilloid subfamily member 1 (TRPV1) for pain control may provide a novel method for pain relief in TMD patients. TRPV1 is primarily expressed on a population of nociceptive-specific neurons and provides a candidate target for the development of pain treatments. Capsaicin is the primary agonist for TRPV1 and has been used previously in relatively low doses (0.025% to 0.075%) as a therapeutic for a variety of pain disorders, including postherpetic neuralgia and osteoarthritis; however, analgesic efficacy remains equivocal. TMD and healthy control subjects were assigned to either an active capsaicin or vehicle control group. The treatments were applied for 2 h and then removed. Quantitative sensory testing (QST) was completed prior to drug application (baseline), 2 h after drug application, and 1 wk later. Perceived pain intensity was measured using a visual analog scale (VAS) following capsaicin or vehicle cream application. Significantly lower pain was reported in the week after application in the capsaicin-treated TMD subjects. For QST measures, there was a decreased thermal pain threshold 2 h after capsaicin application for both the control and TMD groups, but this resolved within a week. Capsaicin had no effect on pressure pain threshold or mechanical sensitivity in both TMD and healthy individuals. This study demonstrates that 8% topical capsaicin therapy is a relatively safe, simple, and effective treatment for patients with TMD. Knowledge Transfer Statement : This study evaluated a novel topical capsaicin therapy for reducing orofacial pain. The results of this study can be used to provide another treatment option for patients with TMD., Competing Interests: The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

Evidence for an association between cortisol and clinical pregnancy in women undergoing In Vitro Fertilisation (IVF) is mixed with previous studies relying exclusively on short term measures of cortisol in blood, saliva, urine, and/or follicular fluid. Hair sampling allows analysis of systemic levels of cortisol over the preceding 3-6 months. The present study sought to explore the relationship between cortisol and clinical pregnancy outcome in women undergoing IVF utilising multiple indices of cortisol derived from both saliva and hair measured prior to commencing gonadotrophin treatment. A total of 135 women (mean age 34.5 SD+/-4.8) were recruited from an English fertility clinic (December 2012-April 2014) 60% of whom became pregnant (n=81). Salivary cortisol data were obtained over two days: upon awakening, 30min post awakening, and at 22:00. A subsample (n=88) of the women providing salivary samples were approached consecutively to provide hair samples for the measurement of cortisol. Independent Logistic regression analyses revealed that salivary cortisol measures including cortisol awakening response (CAR) (p=0.485), area under the curve with respect to ground (AUCg) (p=0.527), area under the curve with respect to increase (AUCi) (p=0.731) and diurnal slope (p=0.889) did not predict clinical pregnancy. In contrast, hair cortisol concentrations significantly predicted clinical pregnancy (p=0.017). Associations between hair cortisol and clinical pregnancy remained when controlling for accumulations of salivary cortisol (p=0.034) accounting for 26.7% of the variance in pregnancy outcome. These findings provide preliminary evidence that longer term systemic cortisol may influence reproductive outcomes; and in turn suggests that interventions to reduce cortisol prior to commencing IVF could improve treatment outcomes., (Copyright © 2016. Published by Elsevier Ltd.)

The first lineage specification during mammalian embryo development can be visually distinguished at the blastocyst stage. Two cell lineages are observed on the embryonic-abembryonic axis of the blastocyst: the inner cell mass and the trophectoderm. The timing and mechanisms driving this process are still not fully understood. In mouse embryos, cells seem prepatterned to become certain cell lineage because the first cleavage plane has been related with further embryonic-abembryonic axis at the blastocyst stage. Nevertheless, this possibility has been very debatable. Our objective was to determine whether this would be the case in another mammalian species, the bovine. To achieve this, cells of in vitro produced bovine embryos were traced from the 2-cell stage to the blastocyst stage. Blastocysts were then classified according to the allocation of the labeled cells in the embryonic and/or abembryonic part of the blastocyst. Surprisingly, we found that there is a significant percentage of the embryos (∼60%) with labeled and nonlabeled cells randomly distributed and intermingled. Using time-lapse microscopy, we have identified the emergence of this random pattern at the third to fourth cell cycle, when cells started to intermingle. Even though no differences were found on morphokinetics among different embryos, these random blastocysts and those with labeled cells separated by the embryonic-abembryonic axis (deviant pattern) are significantly bigger; moreover deviant embryos have a significantly higher number of cells. Interestingly, we observed that daughter cells allocation at the blastocyst stage is not affected by biopsies performed at an earlier stage., (© 2016 by the Society for the Study of Reproduction, Inc.)

Background: Although tobacco control efforts have contributed to an overall decline in smoking, individuals with substance use disorders (SUDs) continue to smoke at high rates and remain targets of advertising to vulnerable groups, including those with mental health disorders and SUDs., Objectives: We examined associations of tobacco advertising exposure and receptivity, anti-tobacco message awareness, and health-risk perception with smoking status and cigarettes-per-day (CPD) in a national sample of SUD treatment patients., Methods: The patients (N = 1,113) in 24 programs chosen randomly, stratified by program type, from among publicly funded adult treatment programs within the National Drug Abuse Treatment Clinical Trials Network completed surveys of smoking, advertising exposure and receptivity, anti-tobacco message awareness, and perceived health risks., Results: Current smokers (77.9% of the sample) smoked a daily median of 10 cigarettes (IQR = 13). The participants reporting daily advertising exposure were 1.41 times more likely to be smokers (p = 0.019) than others. Those highly receptive to advertising were 2.34 times more likely to be smokers (p < 0.001) than those with low/moderate receptivity. Higher perceived health risk was associated with lower odds of smoking (OR = 0.99, 95% CI: 0.98-0.99, p < 0.001). CPD for smokers highly receptive to advertising was 11.1% (95% CI: 2.8%-20.0%) higher than for smokers with low/moderate advertising receptivity. Anti-tobacco message awareness was not associated with smoking status or CPD., Conclusion: The high rate of smoking among SUD treatment patients is associated with daily exposure and high receptivity to tobacco advertisements and lower perception of health-related smoking risks. Tobacco control efforts should target this vulnerable population.

Reproductive management in cattle requires the synchrony of follicle development and oestrus before insemination. However, ovulation of follicles that have not undergone normal physiological maturation can lead to suboptimal luteal function. Here, we investigated the expression of a targeted set of 47 genes in (a) a first-wave vs final-wave dominant follicle (DF; the latter destined to ovulate spontaneously) and (b) 6-day-old corpora lutea (CLs) following either spontaneous ovulation or induced ovulation of a first-wave DF to ascertain their functional significance for competent CL development. Both the mass and progesterone-synthesising capacity of a CL formed following induced ovulation of a first-wave DF were impaired. These impaired CLs had reduced expression of steroidogenic enzymes (e.g. STAR and HSD3B1), luteotrophic receptors (LHCGR) and angiogenic regulators (e.g. VEGFA) and increased expression of BMP2 (linked to luteolysis). Relative to final-wave DFs, characteristic features of first-wave DFs included reduced oestradiol concentrations and a reduced oestradiol:progesterone ratio in the face of increased expression of key steroidogenic enzymes (i.e. CYP11A1, HSD3B1 and CYP19A1) in granulosa cells and reduced expression of the HDL receptor SCARB1 in thecal cells. Transcripts for further components of the TGF and IGF systems (e.g. INHA, INHBA, IGF2R and IGFBP2) varied between the first- and final-wave DFs. These results highlight the importance of hormones such as progesterone interacting with local components of both the TGF and IGF systems to affect the maturation of the ovulatory follicle and functional competency of the subsequent CL., (© 2016 Society for Reproduction and Fertility.)

In this study, we investigated the expression of mucin 1 (MUC1) mRNA and protein in sheep endometrium at different time points during follicular and luteal phases of estrous cycle, and also determined the effect of steroid hormone treatments and interferon tau (IFNτ) on MUC1 mRNA expression in endometrial cell culture in vitro. In experiment one, 15 Welsh mountain ewes were synchronized to a common estrus and killed at precise stages of estrous cycle corresponding to (1) pre-LH peak, (2) LH peak, (3) post-LH peak, (4) early luteal, and (5) mid-luteal. Reproductive tracts were harvested and mRNA was extracted from the endometrial tissues. Parts of the uterine horns were fixed for immunohistochemistry. In experiment two, mixed populations of ovine endometrial cells (from slaughterhouse material collected at the postovulatory stage of the estrous cycle) were cultured to 70% confluence before treatment with (1) progesterone (P4, 10 ng/mL, for 48 hours), (2) estradiol (E2, 100 pg/mL, for 48 hours), or with (3) E2 priming for 12 hours (100 pg/mL) followed by P4 (10 ng/mL) for 36 hours. These were compared with: (4) IFNτ (10 ng/mL, for 48 hours), and (5) basic medium (Dulbecco Modified Eagle Medium /F12) as control. The results showed that MUC1 mRNA and protein expression in sheep endometrium were highest during the midluteal stage and very low during the post-LH period compared with the other stages (P < 0.05). MUC1 immunostaining in the luminal epithelium was apically restricted and was not significantly different across all stages of estrous cycle except at the post-LH peak where it was significantly low. In cell culture, MUC1 mRNA expression was significantly upregulated by both steroids either singly or in combination (P < 0.05), and downregulated in the presence of IFNτ. In conclusion, endometrial MUC1 expression is cyclically regulated by both E2 and P4in vivo and in vitro, and directly downregulated by IFNτ treatment in vitro., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine the accuracy of ultrasound in the diagnosis of a tubal ectopic pregnancy in the absence of an obvious extrauterine embryo., Methods: This was a systematic review conducted in accordance with the PRISMA statement and registered with PROSPERO. We searched MEDLINE, EMBASE and The Cochrane Library for relevant citations from database inception to July 2014. Studies were selected in a two-stage process and their data extracted by two reviewers. Accuracy measures were calculated for each ultrasound sign, i.e. empty uterus, pseudosac, adnexal mass and free fluid in the pouch of Douglas, alone and in various combinations. Individual study estimates were plotted in summary receiver-operating characteristics curves and forest plots for examination of heterogeneity. The quality of included studies was assessed., Results: Thirty-one studies including 5858 women were selected from 19,959 citations. Following meta-analysis, an empty uterus on ultrasound was found to predict an ectopic pregnancy with a sensitivity of 81.1% (95% CI, 42.1-96.2%) and specificity of 79.5% (95% CI, 68.9-87.1%). The corresponding performance of the pseudosac, adnexal mass and free fluid were: 5.5% (95% CI, 3.3-9.0%) and 94.2% (95% CI, 75.9-98.8%); 63.5% (95% CI, 48.5-76.3%) and 91.4% (95% CI, 83.6-95.7%); and 47.2% (95% CI, 33.2-61.7%) and 92.3% (95% CI, 85.6-96.0%), respectively., Conclusion: Visualization of an empty uterus, adnexal mass, free fluid or a pseudosac has poor sensitivity for the diagnosis of a tubal pregnancy when an obvious extrauterine embryo is absent, but it has good specificity. We can therefore infer that ultrasound is more useful for 'ruling in' a tubal pregnancy than 'ruling out' one. However, the findings were limited by the poor quality of some included studies and heterogeneity in the index test and reference standard., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Differential regulation of LHR in theca cells (TC) and granulosa cells (GC) is important for normal follicular development. Unlike TC, GC only acquire LH-responsiveness during the later stages of antral follicle development. This study tested the hypothesis that differential LH-responsiveness in these two cell types may be due, in part, to shifts in cellular patterns of alternatively spliced LHR mRNA transcripts which may not be obvious from analysis of total LHR gene expression. It also further explored the role of translation inhibition by an LHR binding protein (LHBP), normally associated with the production of endogenous cholesterol. LHR mRNA variation arises as a result of the alternative splicing of two variable deletion sites (VDS) designated 5' VDS and 3' VDS, and it was proposed that differences in cell sensitivity to LH may be due in part to variations in the pattern of the mRNA expression of the receptor variants. The outcomes of the present study support a dynamic multi-facetted regulation of LHR during pre-translation. Not only did the ratio between variants change during antral follicle growth and in vitro cell differentiation but also between TC and GC. Regulation could also be linked to LH concentration feedback mechanisms as the absence of LH caused cultured TC to markedly up-regulate amounts of LHR mRNA. In both TC and GC, LHR mRNA was greatly reduced after treatment to block mevalonate production in the de novo cholesterol pathway, adding further support for a regulatory mechanism linked to enriched cellular amounts of mevalonate kinase., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Our aim in the study described here was to assess the feasibility of spatiotemporal image correlation power Doppler quantification of the endometrium with two techniques: spherical samples and whole tissue. We scanned 51 women in the midluteal phase of the menstrual cycle: STIC assessment of the whole endometrium was not possible in 10% of cases, whereas spherical analysis was possible in all. The time taken for data set analysis was much longer for the whole endometrium compared with spherical analysis (1478.9 ± 291 s vs. 266.8 ± 39.3 s, p < 0.05). Intra-class correlation coefficients for the vascularization flow index (VFI) were similar for both methods. Volumetric vascularity indices were higher when spherical sampling was conducted. Significant cycle-to-cycle variability in the vascularity indices was present, with coefficients of variation exceeding 20% for both techniques. We found that STIC power Doppler quantification of the whole endometrium is possible in the majority of cases, however, it is time consuming and limited by significant cycle-to-cycle variability., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the diagnostic accuracy of ultrasound in predicting the location of an intrauterine pregnancy before visualization of the yolk sac is possible., Methods: This was a systematic review conducted in accordance with the PRISMA statement and registered with PROSPERO. We searched MEDLINE, EMBASE and The Cochrane Library for relevant citations. Studies were selected in a two-stage process and their data extracted by two reviewers. Accuracy measures were calculated for each ultrasound sign, i.e. gestational sac, double decidual sac sign, intradecidual sign, chorionic rim sign and yolk sac. Individual study estimates were plotted in summary receiver-operating characteristics curves and forest plots for examination of heterogeneity. The quality of included studies was assessed., Results: Seventeen studies including 2564 women were selected from 19 959 potential papers. Following meta-analysis, the presence of a gestational sac on ultrasound examination was found to predict an intrauterine pregnancy with a sensitivity of 52.8% (95% CI, 38.2-66.9%) and specificity of 97.6% (95% CI, 94.3-99.0%). The corresponding performance of the double decidual sac sign, intradecidual sign, chorionic rim sign and yolk sac were: 81.8% (95% CI, 68.1-90.4%) and 97.3% (95% CI, 76.1-99.8%); 66.1% (95% CI, 58.9-72.8%) and 100% (95% CI, 91.0-100%); 79.9% (95% CI, 73.0-85.7%) and 97.1% (95% CI, 89.9-99.6%); and 42.2% (95% CI, 27.7-57.9%) and 100% (95% CI, 54.1-100%), respectively., Conclusion: Visualization of a gestational sac, double decidual sac sign, intradecidual sign or chorionic rim sign increases the probability of an intrauterine pregnancy but is not as accurate for diagnosis as the detection of the yolk sac. However, the findings were limited by the small number and poor quality of the studies included and heterogeneity in the index test and reference standard., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

This study examined associations of therapeutic alliance and treatment delivery fidelity with treatment retention in Stimulant Abusers to Engage in Twelve-Step (STAGE-12), a community-based trial of 12-Step Facilitation (TSF) conducted within the National Drug Abuse Treatment Clinical Trials Network (CTN). The STAGE-12 trial randomized 234 stimulant abusers enrolled in 10 outpatient drug treatment programs to an eight-session, group and individual TSF intervention. During the study, TSF participants rated therapeutic alliance using the Helping Alliance questionnaire-II. After the study, independent raters evaluated treatment delivery fidelity of all TSF sessions on adherence, competence, and therapist empathy. Poisson regression modeling examined relationships of treatment delivery fidelity and therapeutic alliance with treatment retention (measured by number of sessions attended) for 174 participants with complete fidelity and alliance data. Therapeutic alliance (p = .005) and therapist competence (p = .010) were significantly associated with better treatment retention. Therapist adherence was associated with poorer retention in a nonsignificant trend (p = .061). In conclusion, stronger therapeutic alliance and higher therapist competence in the delivery of a TSF intervention were associated with better treatment retention whereas treatment adherence was not. Training and fidelity monitoring of TSF should focus on general therapist skills and therapeutic alliance development to maximize treatment retention. (PsycINFO Database Record, ((c) 2015 APA, all rights reserved).)

Background: The temporal and situational stability of personality has led generations of researchers to hypothesize that personality may have enduring effects on health, but the biological mechanisms of such relationships remain poorly understood. In the present study, we utilized a functional genomics approach to examine the relationship between the 5 major dimensions of personality and patterns of gene expression as predicted by 'behavioural immune response' theory. We specifically focussed on two sets of genes previously linked to stress, threat, and adverse socio-environmental conditions: pro-inflammatory genes and genes involved in Type I interferon and antibody responses., Methods: An opportunity sample of 121 healthy individuals was recruited (86 females; mean age 24 years). Individuals completed a validated measure of personality; questions relating to current health behaviours; and provided a 5ml sample of peripheral blood for gene expression analysis., Results: Extraversion was associated with increased expression of pro-inflammatory genes and Conscientiousness was associated with reduced expression of pro-inflammatory genes. Both associations were independent of health behaviours, negative affect, and leukocyte subset distributions. Antiviral and antibody-related gene expression was not associated with any personality dimension., Conclusions: The present data shed new light on the long-observed epidemiological associations between personality, physical health, and human longevity. Further research is required to elucidate the biological mechanisms underlying these associations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Study Question: What are the consequences of polycystic ovary syndrome (PCOS) pathology and metformin-pretreatment in vivo in women with PCOS on the metabolism and steroid production of follicular phenotype- and long-term cultured-granulosa cells (GC)?, Summary Answer: PCOS pathology significantly compromised glucose metabolism and the progesterone synthetic capacity of follicular- and long-term cultured-GCs and the metabolic impact of PCOS on GC function was alleviated by metformin-pretreatment in vivo., What Is Known Already: Granulosa cells from women with PCOS have been shown to have an impaired insulin-stimulated glucose uptake and lactate production in vitro. However, these results were obtained by placing GCs in unphysiological conditions in culture medium containing high glucose and insulin concentrations. Moreover, existing data on insulin-responsive steroid production in vitro by PCOS GCs vary., Study Design, Size and Duration: Case-control experimental research comparing glucose uptake, pyruvate and lactate production and progesterone production in vitro by GCs from three aetiological groups, all undergoing IVF; healthy control women (Control, n = 12), women with PCOS treated with metformin in vivo (Metformin, n = 8) and women with PCOS not exposed to metformin (PCOS, n = 8). The study was conducted over a period of 3 years between 2007 and 2010., Participants/materials, Setting, Methods: Rotterdam criteria were used for the diagnosis of PCOS; all subjects were matched for age, BMI and baseline FSH. Individual patient cultures were undertaken with cells incubated in a validated, physiological, serum-free culture medium containing doses of 0-6 mM glucose and 0-100 ng/ml insulin for 6 h and 144 h to quantify the impact of treatments on acute and long-term metabolism, respectively, and progesterone production. The metabolite content of spent media was measured using spectrophotometric plate reader assay. The progesterone content of spent media was measured by enzyme-linked immunosorbent assay. Viable GC number was quantified after 144 h of culture by the vital dye Neutral Red uptake assay., Main Results and the Role of Chance: Granulosa cells from women with PCOS pathology revealed reduced pyruvate production and preferential lactate production in addition to their reduced glucose uptake during cultures (P < 0.05). Metformin pretreatment alleviated this metabolic lesion (P < 0.05) and enhanced cell proliferation in vitro (P < 0.05), but cells retained a significantly reduced capacity for progesterone synthesis compared with controls (P < 0.05)., Limitations, Reasons for Caution: Although significant treatment effects were detected in this small cohort, further studies are required to underpin the molecular mechanisms of the effect of metformin on GCs., Wider Implications of the Findings: The individual patient culture strategy combined with multifactorial experimental design strengthens the biological interpretation of the data. Collectively, these results support the notion that there is an inherent impairment in progesterone biosynthetic capacity of the GCs from women with PCOS. The positive, acute metabolic effect and the negative long-term steroidogenic effect on GCs following metformin exposure in vivo may have important implications for follicular development and luteinized GC function when the drug is used in clinical practice., Study Funding/competing Interests: No competing interests. This work was supported by the UK Medical Research Council Grant Reference number G0800250., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Introduction: Dehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a limited number of randomised controlled trials (RCTs). This double-blinded RCT aims to measure the effect of DHEA supplementation prior to and during controlled ovarian hyperstimulation on ovarian response prior to IVF treatment in women predicted to have poor ovarian reserve., Methods and Analysis: Sixty women with ovarian antral follicle count ≤10 and serum anti-Mullerian hormone ≤5 pmol/L undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment at the Nurture fertility clinic, Nottingham will be recruited. They will be randomised to either receive DHEA capsule 75 mg/day or placebo for at least 12 weeks before egg collection. All participants will undergo standard long down regulation protocol using human menopausal gonadotropin 300 IU/day. Serum samples and follicular fluids at the time of egg collection will be collected for hormonal immunoassays. For ICSI participants, cumulus cells stripped from oocyte will be collected for cumulus gene expression analyses regarding oocyte competence. Microdrops of oocyte culture media before the time of ICSI will be assessed for glucose, pyruvate and lactate utilisation. Embryo transfer will be performed on day 2, 3 or 5 based on the number and quality of the embryos available. Pregnancy will be defined as urine pregnancy test positive (biochemical pregnancy) and 6-8 weeks ultrasound scan with fetal heart beat (clinical pregnancy) and live birth. It is planned to perform the molecular and nutritional fingerprint analyses in batches after finishing the clinical phase of the study., Ethics and Dissemination: The approval of the study was granted by the NHS Research Ethics Committee (Ref number NRES 12/EM/0002), the Medicines and Healthcare products Regulatory Agency (MHRA), and the Nottingham University Hospitals Trust Research and Development department. All participants shall provide written informed consent before being randomised into allocated treatment groups., Trial Registration Number: Protocol V.2.0; EudraCT number: 2011-002425-21; http://www.clinicaltrials.gov; NCT01572025; CTA reference: 03057/0053/001-0002., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

This study investigated the correspondence among four groups of raters on adherence to STAGE-12, a manualized 12-step facilitation (TSF) group and individual treatment targeting stimulant abuse. The four rater groups included the study therapists, supervisors, study-related ("TSF expert") raters, and non-project related ("external") raters. Results indicated that external raters rated most critically mean adherence - the mean of all the adherence items - and global performance. External raters also demonstrated the highest degree of reliability with the designated expert. Therapists rated their own adherence lower, on average, than did supervisors and TSF expert raters, but therapist ratings also had the poorest reliability. Findings highlight the challenges in developing practical, but effective methods of fidelity monitoring for evidence based practice in clinical settings. Recommendations based on study findings are provided., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The primary aims of this study were to utilize a specialized culture system to further elucidate the functional significance of pericellular hypoxia within the granulosa cell (GC) compartment of growing follicles, and to clarify its effects on the production of vascular endothelial growth factor (VEGF)-A isoforms and steroid hormones. Multilaminar clusters formed rapidly in ovine GCs seeded at high density (HD), and Hypoxyprobe-1 protein adducts appeared markedly more abundant and HIF-1 activation significantly (P < 0.001) greater than in cells seeded at low density (LD). Four proangiogenic VEGF mRNA transcript variants were identified in cultured GCs. Most abundant were VEGF120 and VEGF164, but VEGF182 and VEGF188 were also detected. Total VEGF mRNA was shown to be up-regulated transiently in the HD cells (P < 0.001) and VEGF164 mRNA appeared to contribute most to this. The hypoxia mimetic cobalt chloride also induced marked increases in HIF-1 activation (P < 0.01) and total VEGF mRNA (P < 0.01) production. HD cells increased levels of HIF-1alpha (P < 0.001) and VEGF receptor type 1 (P < 0.05), but not VEGF receptor type 2 mRNA, compared to LD cells or cells grown under chemically induced hypoxia. Both 17beta-estradiol (E2) and progesterone (P4) were markedly lower (P < 0.001) in the HD, cells but though cobalt chloride treatment accompanied significantly reduced P4 production (P < 0.05), E2 levels remained similar to those in untreated cells. These outcomes suggest that pericellular hypoxia may be an important mediator of VEGF production in the GCs of growing follicles, but that local regulation is complex and may involve multiple mechanisms such as mediation by steroid hormones and differential variant mRNA production., (© 2014 by the Society for the Study of Reproduction, Inc.)

Study Question: Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)?, Summary Answer: Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes., What Is Known Already: Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells., Study Design, Size, Duration: Study 1 (2010-2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7-8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7-9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011-2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane(®); n = 8) or eptifibatide (Integrilin(®); n = 8) on ovarian function and fertility 11-23 months after WOCP&TP., Participants/materials, Setting, Methods: Both studies utilized mature, parous, Greyface ewes aged 3-6 years and weighing 50-75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology., Main Results and the Role of Chance: In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP., Limitations, Reasons for Caution: Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure., Wider Implications of the Findings: This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue., Study Funding/competing Interests: Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Objective: To investigate the effect of assisted reproductive technology (ART) treatments on the sex ratio of babies born., Design: Assessment of direct effects of assisted conception through retrospective data analysis on the progeny sex ratio of treated women in the United Kingdom., Setting: The study uses the anonymized register of the Human Fertilisation and Embryology Authority., Patient(s): A total of 106,066 babies of known gender born to 76,994 treated mothers and 85,511 treatment cycles between 2000 and 2010 in the United Kingdom., Intervention(s): Intrauterine insemination, IVF, or intracytoplasmic sperm injection (ICSI)., Main Outcome Measure(s): Sex ratio of babies born., Result(s): Intrauterine insemination, IVF, and ICSI lead to different sex ratios, highest after IVF (proportion male = mean 0.521 ± confidence interval 0.0056) and lowest under ICSI embryo transfer (0.493 ± 0.0031). In addition, for both ICSI and IVF, transferring embryos at a later stage (blastocyst) results in approximately 6% more males than after early cleavage-stage ET., Conclusion(s): Because the cumulative number of IVF babies born is increasing significantly in Britain and elsewhere, more research is needed into the causes of gender bias after ART and into the public health impact of such gender bias of offspring born observed on the rest of the population., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Recurrent implantation failure (RIF) is an iatrogenic condition, being the result of repetitive unsuccessful cycles of IVF or intracytoplasmic sperm injection (ICSI) treatment. The aim of this review was to assess the definitions of RIF used in literature as well as suggest a uniform definition of this condition. A systematic search of MEDLINE, Embase and Cochrane Library was conducted. The most commonly stated definitions described RIF as 'three or more failed treatment cycles' or 'two or more failed cycles'. Other identified definitions were based solely on the number of embryos transferred in previous cycles or combined the number of previously failed cycles with the number of transferred embryos. Several other definitions were also identified. This review highlights the lack of uniformity of the definition of RIF. Based on the available literature and the expert opinion of the authors, RIF should be defined as the absence of implantation after two consecutive cycles of IVF, ICSI or frozen embryo replacement cycles where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, with all embryos being of good quality and of appropriate developmental stage., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

This study evaluated whether 3D power Doppler (3DPD) indices from endometrium and subendometrium can identify increases in endometrial volume/vascularity induced by exogenous oestradiol and subsequent introduction of progestogens in women undergoing frozen-thawed embryo transfer (FET). Oral oestradiol was administered at increasing doses after down-regulation to prepare the endometrium and progestogens were used for luteal support. 3DPD data sets were acquired at down-regulation, on days 5, 10 and 15 of oestradiol administration and at the time of FET. Endometrial thickness was measured using the multiplanar method and endometrial volume and blood flow from the endometrium and subendometrium were estimated using virtual organ computer-aided analysis and shell-imaging. This study evaluated 45 women at least once: 19 achieved clinical pregnancy (CP); 21 were evaluated at down-regulation (eight CP), 26 at day 5 (10 CP), 31 at day 10 (12 CP), 31 at day 15 (13 CP) and 16 at FET (seven CP). Changes were observed in all parameters between the examinations; however, differences between women who achieved CP and those who did not were not significant. 3DPD angiography is not a sufficiently sensitive tool to predict the outcome of FET. We evaluate whether 3D ultrasound using power Doppler (3DPD) indices from endometrium and subendometrium can identify predictable increases in endometrial volume and vascularity induced by serial increments in exogenous oestradiol and the subsequent introduction of progestogens in women undergoing frozen-thawed embryo transfer (FET) using hormone replacement therapy to prepare the endometrium. Oral oestradiol was administered at increasing doses after down-regulation to prepare the endometrium and progestogens were used for luteal support. 3DPD data sets of the uterus were acquired at down-regulation, on days 5, 10, and 15 of oestradiol administration, and at the time of FET. Endometrial thickness was measured. Endometrial volume and blood flow from the endometrium and subendometrium were measured using virtual organ computer-aided analysis (VOCAL) and shell imaging. This study evaluated 45 women at least once: 19 achieved clinical pregnancy (CP); 21 were evaluated at down-regulation (eight CP), 26 at day 5 (10 CP), 31 at day 10 (12 CP), 31 at day 15 (13 CP) and 16 at FET (seven CP). Changes were observed in all the parameters between the examinations; however, differences between women who achieved CP and those who did not were not significant, suggesting that quantitative 3D power Doppler angiography is not a sufficiently sensitive tool to predict the outcome of FET treatment., (Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The aim of the present study was to investigate the effects of glucose, galactose and fructose on the LH-induced differentiation and mRNA expression of sugar transport facilitators (SLC2A) by sheep thecal cells derived from small antral follicles cultured under serum-free conditions for 6 days. The dose and type of monosaccharide had a significant effect on LH-induced androstenedione production by theca cells and there was a significant interaction (P<0.001). Glucose and galactose were used with equal efficiency so that cell numbers and androstenedione production at the end of the culture were comparable. Pharmacological doses of glucose (16.7 mM) inhibited steroidogenesis (P<0.05). Cell numbers and androstenedione production by cells cultured with fructose were lower than for cells cultured with either glucose or galactose (P<0.001). None of the monosaccharides resulted in the production of lactate. Expression of SLC2A1, SLC2A4 and SLC2A8, but not SLC2A5, mRNA was detected in fresh and cultured theca cells. Large doses (16.7 mM) of glucose and fructose, but not galactose, suppressed (P<0.05) SLC2A expression. The results show that glucose and galactose, but not fructose, are readily metabolised via oxidative pathways to support LH-induced differentiation of sheep theca cells. Further work is required to determine the mechanisms resulting in these differences in relation to the established effects of nutrition on reproductive function.

Objective: To assess the relationship between the ethnicity of women and the clinical success of in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment., Design: Observational cohort study., Setting: Nottingham University Research and Treatment Unit in Reproduction (NURTURE), UK., Sample: A total of 1517 women, of which 1291 were white Europeans and 226 belonged to an ethnic minority group. All the women were undergoing their first cycle of assisted reproductive technology (ART) between 2006 and 2011., Methods: All of the women underwent their first cycle of ART between 2006 and 2011., Main Outcome Measures: Live birth rates following IVF or ICSI treatment., Results: Although pre-treatment ovarian reserve variables [mean age, basal follicle stimulating hormone (FSH), and total antral follicle count] were significantly favourable in the ethnic group, the live birth rates were significantly lower in this group (35%) compared with the white European group (43.8%) (relative risk 0.8; 95% CI 0.66-0.97). On logistic regression analysis, ethnicity was an independent predictor of live birth rate (OR 0.688; 95% CI 0.513-0.924). After controlling for the other independent variables (age and FSH), the significant association between ethnicity and live birth rate remained strong (OR 0.591; 95% CI 0.425-0.822) on multivariate logistic regression analysis., Conclusions: Live birth rates following IVF or ICSI treatment were significantly lower in the ethnic minority group compared with white European women, which suggests that ethnicity is a major determinant of live birth following IVF treatment., (© 2013 Royal College of Obstetricians and Gynaecologists.)

Study Question: What are the effects of exposure of ovarian tissue to dehydroepiandrosterone (DHEA) supplementation in vivo?, Summary Answer: DHEA exposure stimulates initiation of primordial follicles and development of gonadotrophin-responsive preantral/early antral follicles possibly mediated through promoting granulosa cell proliferation and enhancing anti-Mullerian hormone (AMH) expression. WHAT IS KNOWN ALREADY?: Ovarian ageing is a cause of subfertility and is associated with poor outcomes of IVF treatment and premature menopause. A few clinical studies have shown that DHEA can improve ovarian response and increase the chances of pregnancy after IVF treatment in women with a diminished ovarian reserve (DOR) suggesting DHEA may help to overcome the effect of ovarian ageing. However, there are no data about how DHEA acts on ovarian folliculogenesis., Study Design, Size and Duration: A cortical autograft experimental model was conducted in six female sheep aged at least 24 months. The period of DHEA treatment in the animals lasted for 10 weeks., Participants/materials, Setting, Methods: All the animals were subjected to unilateral oophorectomy. Half of the ovary was fixed for histological analysis as a time-zero control. The remaining tissue was used to isolate patches of ovarian cortex which were autografted back onto the ovarian pedicle. The grafting procedure eradicated all growing follicles and synchronized early follicular development. After a 10-week treatment period with DHEA implants, the ewes were sacrificed and the graft and remaining ovary were harvested. Histological and immunohistochemistry (IHC) findings, accompanied with serum hormonal profiles were compared to determine the effect on the follicle population., Main Results and the Role of Chance: Higher proportions of the follicle population in the remaining ovary were observed to be in the antral stage after DHEA treatment. The observation coincided with an increase in the rate of primordial follicle initiation and preantral follicle development in cortical grafts and the remaining ovarian tissue, respectively. The IHC results indicated that DHEA increased the expression of both the proliferation marker (KI-67) in granulosa cells and the follicular AMH expression at the preantral and early antral follicle stages., Limitations, Reasons for Caution: The experimental design compared follicle populations before and after DHEA treatment within individual animals to allow changes over time to be detected against a background of high inter-animal variation. However, since no controls without DHEA were included, we cannot say what would have happened over time in its absence, and it is possible that other factors may have resulted in the changes in follicle development observed during the experiment., Wider Implications of the Finding: Our data supports the idea that DHEA might be a useful therapy to delay the effects of ovarian ageing. Therefore, it may have a role as an adjunct during IVF to improve ovarian response in women with DOR and as a treatment for premature ovarian insufficiency., Study Funding/competing Interest(s): The research received finance support from the University of Nottingham. The authors declare no conflict of interest in this study.