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Cassidy Nguyen,1,* Guilherme Kuceki,1,* Michael Birdsall,1 Dev Ram Sahni,2,3 Vikram Nath Sahni,2 Christopher M Hull2 1School of Medicine, University of Utah, Salt Lake City, UT, USA; 2Department of Dermatology, University of Utah Health, Salt Lake City, UT, USA; 3Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Dev Ram Sahni, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA, 02115, USA, Tel +16177324918, Email sahnidr@alumni.vcu.eduAbstract: Rosacea is a common chronic dermatosis. Clinically, rosacea can present with flushing, erythema, papules, pustules, telangiectasias, phymatous changes, pruritus, burning, and stinging. In 2017, the National Rosacea Society Expert Committee recommended a phenotype-based classification for therapy. In this review, we identify monotherapies and multimodal treatment approaches for the clinical management of rosacea including topical, systemic, laser and light, alternative, and combination therapies.Keywords: combination therapy, management, monotherapy, rosacea, therapy, treatment

A randomized, controlled, double-blind, double-dummy, phase III clinical trial was conducted in 84 women to compare the efficacy of a s.c. injection of 250 microg recombinant human chorionic gonadotrophin (rHCG; Ovidrel) to an i.m. injection of 5000 IU urinary HCG (uHCG; Profasi) in inducing folliculogenesis, resumption of oocyte meiosis and luteinization after ovulation induction with recombinant follicle stimulating hormone (Gonal-F). The study primary endpoint was comparison of the number of oocytes retrieved per patient receiving either compound. Secondary comparisons included the number of oocytes retrieved per follicles aspirated; the number of mature oocytes; normally fertilized oocytes; and cleaved embryos. There were no statistically significant differences between groups for the primary endpoint (mean +/- SD oocytes retrieved 10.8 +/- 4.5 for rHCG versus 10.3 +/- 5.1 for uHCG) or each of the secondary endpoints except for increased concentrations of progesterone 6-7 days after rHCG administration (353.2 +/- 215.1 versus 234.1 +/- 129.4 nmol/l; P < 0. 004) and for HCG during the luteal phase following rHCG (P < 0.02). There were also no significant side-effects for either drug. Since the confidence intervals for the difference of the number of oocytes retrieved between the two treatment groups were within the bounds defined by the multi-trial protocol equivalence between rHCG and uHCG could be declared. [ABSTRACT FROM AUTHOR]

The pheromone N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) regulates expression of bioluminescence In the marine bacterium Vibrio fischeri, the production of carbapenem antibiotic in Erwinia carotovora and exoenzymes in both E. carotovora and Pseudomonas aeruginosa. A characteristic feature of this regulatory mechanism in V. fischeri is that it is cell density-dependent, reflecting the need to accumulate sufficient pheromone to trigger the induction of gene expression. Using a lux plasmid-based bioluminescent sensor for OHHL, pheromone production by E. carotovora, Enterobacter agglomerans, Hafnia alvei, Rahnella aquatilis and Serratia marcescens has been demonstrated and shown also to be cell density-dependent. Production of OHHL implies the presence in these bacteria of a gene equivalent to luxl. Chromosomal banks from all five enteric bacteria have yielded clones capable of eliciting OHHL production when expressed in Escherichia coli. The luxl homologue from both E. carotovora (carl) and E. agglomerans (eagl) were characterized at the DNA sequence level and the deduced protein sequences have only 25% identity with the V. fischeri Luxl. Despite this, carl, eagl and luxl are shown to be biologically equivalent. An insertion mutant of eagl demonstrates that this gene is essential for OHHL production in E. agglomerans. [ABSTRACT FROM AUTHOR]

Background: Despite international evidence about fertility preservation (FP), several barriers still prevent the implementation of equitable FP practice. Currently, oncofertility competencies do not exist. The aim of this study was to develop an oncofertility competency framework that defines the key components of oncofertility care, develops a model for prioritizing service development, and defines the roles that health care professionals (HCPs) play., Materials and Method: A quantitative modified Delphi methodology was used to conduct two rounds of an electronic survey, querying and synthesizing opinions about statements regarding oncofertility care with HCPs and patient and family advocacy groups (PFAs) from 16 countries (12 high and 4 middle income). Statements included the roles of HCPs and priorities for service development care across ten domains (communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, oncofertility training, reproductive survivorship care and fertility-related psychosocial support, supportive care, and ethical frameworks) that represent 33 different elements of care., Results: The first questionnaire was completed by 457 participants (332 HCPs and 125 PFAs). One hundred and thirty-eight participants completed the second questionnaire (122 HCPs and 16 PFAs). Consensus was agreed on 108 oncofertility competencies and the roles HCPs should play in oncofertility care. A three-tier service development model is proposed, with gradual implementation of different components of care. A total of 92.8% of the 108 agreed competencies also had agreement between high and middle income participants., Conclusion: FP guidelines establish best practice but do not consider the skills and requirements to implement these guidelines. The competency framework gives HCPs and services a structure for the training of HCPs and implementation of care, as well as defining a model for prioritizing oncofertility service development., Implications for Practice: Despite international evidence about fertility preservation (FP), several barriers still prevent the implementation of equitable FP practice. The competency framework gives 108 competencies that will allow health care professionals (HCPs) and services a structure for the development of oncofertility care, as well as define the role HCPs play to provide care and support. The framework also proposes a three-tier oncofertility service development model which prioritizes the development of components of oncofertility care into essential, enhanced, and expert services, giving clear recommendations for service development. The competency framework will enhance the implementation of FP guidelines, improving the equitable access to medical and psychological oncofertility care., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background: Fertility preservation (FP) is an important quality of life issue for cancer survivors of reproductive age. Despite the existence of broad international guidelines, the delivery of oncofertility care, particularly amongst paediatric, adolescent and young adult patients, remains a challenge for healthcare professionals (HCPs). The quality of oncofertility care is variable and the uptake and utilization of FP remains low. Available guidelines fall short in providing adequate detail on how oncofertility models of care (MOC) allow for the real-world application of guidelines by HCPs., Objective and Rationale: The aim of this study was to systematically review the literature on the components of oncofertility care as defined by patient and clinician representatives, and identify the barriers, facilitators and challenges, so as to improve the implementation of oncofertility services., Search Methods: A systematic scoping review was conducted on oncofertility MOC literature published in English between 2007 and 2016, relating to 10 domains of care identified through consumer research: communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, training, supportive care during treatment, reproductive care after cancer treatment, psychosocial support and ethical practice of oncofertility care. A wide range of electronic databases (CINAHL, Embase, PsycINFO, PubMed, AEIPT, Education Research Complete, ProQuest and VOCED) were searched in order to synthesize the evidence around delivery of oncofertility care. Related citations and reference lists were searched. The review was undertaken following registration (International prospective register of systematic reviews (PROSPERO) registration number CRD42017055837) and guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)., Outcomes: A total of 846 potentially relevant studies were identified after the removal of duplicates. All titles and abstracts were screened by a single reviewer and the final 147 papers were screened by two reviewers. Ten papers on established MOC were identified amongst the included papers. Data were extracted from each paper and quality scores were then summarized in the oncofertility MOC summary matrix. The results identified a number of themes for improving MOC in each domain, which included: the importance of patients receiving communication that is of a higher quality and in different formats on their fertility risk and FP options; improving provision of oncofertility care in a timely manner; improving access to age-appropriate care; defining the role and scope of practice of all HCPs; and improving communication between different HCPs. Different forms of decision aids were found useful for assisting patients to understand FP options and weigh up choices., Wider Implications: This analysis identifies core components for delivery of oncofertility MOC. The provision of oncofertility services requires planning to ensure services have safe and reliable referral pathways and that they are age-appropriate and include medical and psychological oncofertility care into the survivorship period. In order for this to happen, collaboration needs to occur between clinicians, allied HCPs and executives within paediatric and adult hospitals, as well as fertility clinics across both public and private services. Training of both cancer and non-cancer HCPs is needed to improve the knowledge of HCPs, the quality of care provided and the confidence of HCPs with these consultations., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

This paper examines the definition of the terms "food" and "drug" as used in the Food, Drug and Cosmetic Act through the lens of biopharmed products. The paper uses the so-called "banana vaccine" as a case study to highlight the problems that occur when attempting to regulate a product that could be safely used as a food or as a drug. Specifically, the examination of this model illustrates the problems in the current definitional scheme. The paper considers how a product that straddles the definitional line between food and drug could be regulated and proposes a reformation to how the definitions are applied to products to better suit new technology in food and drugs.

Objective: This pilot investigation was undertaken to assess the efficacy of low-dose aspirin therapy for the treatment of women with antiphospholipid antibodies when recurrent miscarriage is the only sequela., Study Design: A double-blind, randomized, placebo-controlled trial was conducted in the setting of the recurrent miscarriage clinic of a tertiary referral obstetric hospital. The participants were 50 women with a history of recurrent miscarriages (>/=3) and antiphospholipid antibodies. Women with systemic lupus erythematosus or a history of thrombosis were excluded. Women were recruited after full investigative screening at the recurrent miscarriage clinic. Women with >/=3 fetal losses and persistently positive results for antiphospholipid antibodies were randomly allocated to receive either aspirin (75 mg daily) or placebo. Investigators, clinicians, and patients were blinded to the treatment. Rates of live births, antenatal complications, and delivery and neonatal outcomes were recorded prospectively. Data were compared by chi(2) analysis with Yates' correction, the Fisher exact test, or the Student t test as appropriate., Results: There were 10 exclusions after random assignment because of inappropriate inclusion. Eighty-five percent of the placebo (17/20) group and 80% of the aspirin-treated group (16/20) were delivered of live infants. This difference was not significant. There were no significant differences in antenatal complications or neonatal morbidity between the groups., Conclusions: This preliminary study suggests that low-dose aspirin has no additional benefit when added to supportive care for women for whom recurrent early fetal loss is the only sequela of the antiphospholipid syndrome. This live birth rate with supportive care alone exceeds the published live birth rates for women with antiphospholipid antibody-mediated recurrent fetal loss who were treated with heparin or corticosteroids. This trial, like all other trials in this field, is small, but its results bring into question the need for pharmacologic intervention for women with antiphospholipid syndrome for whom recurrent fetal loss is the only sequela. Our results highlight the need for a large randomized controlled trial to identify the optimal treatment for this group of women and justify the inclusion of a placebo arm in any such trial.

We have studied the effects of the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on Huntington's disease (HD) gene transcription in neuronal and non-neuronal cell lines, to investigate pathways regulating HD gene expression. TPA reduced transcription from the HD gene promoter in SK-N-SH (neuroblastoma) and HeLa cells but not in JEG3 (choriocarcinoma) cells. In SK-N-SH cells, the responsible cis-acting promoter sequences comprise the tandemly duplicated Sp1 sites in the region from -213 to -174, relative to the translation start site. The TPA-down-regulating region in HeLa cells was mapped to the sequence from -141 to -126. In conclusion, this demonstrates that HD gene transcription can be down-regulated in vitro in a cell-specific manner.

Jacobsen syndrome is a haploinsufficiency disorder caused, most frequently by terminal deletion of part of the long arm of chromosome 11, with breakpoints in 11q23.3-11q24.2. Inheritance of an expanded p(CCG)n trinucleotide repeat at the folate-sensitive fragile site FRA11B has been implicated in the generation of the chromosome breakpoint in several Jacobsen syndrome patients. The majority of such breakpoints, however, map distal to this fragile site and are not linked with its expression. To characterize these distal breakpoints and ultimately to further investigate the mechanisms of chromosome breakage, a 40-Mb YAC contig covering the distal long arm of chromosome 11 was assembled. The utility of the YAC contig was demonstrated in three ways: (1) by rapidly mapping the breakpoints from two new Jacobsen syndrome patients using FISH; (2) by demonstrating conversion to high resolution PAC contigs after direct screening of PAC library filters with a YAC clone containing a Jacobsen syndrome breakpoint; and (3) by placing 23 Jacobsen syndrome breakpoints on the physical map. This analysis has suggested the existence of at least two new Jacobsen syndrome breakpoint cluster regions in distal chromosome 11.

Recent studies show that high concentrations of inhibin A and activin A are present in the maternal serum throughout human pregnancy. The aim of this study was to determine whether the corpus luteum produces significant quantities of inhibin A and activin A during the first trimester of pregnancy. This prospective study examined two groups of women who had blood samples taken from 5-12 weeks gestation. One group consisted of 14 women with donor egg pregnancies (8 singletons and 6 multiples) who did not have corpora lutea, and the other group consisted 5 women with spontaneous pregnancies who had corpora lutea. Inhibin A and activin A were measured at weekly intervals using specific enzyme immunoassays. All pregnancies progressed to term, with healthy babies being delivered. Maternal serum concentrations of inhibin A significantly increased throughout the study period in the donor egg pregnancies (P < 0.001) and the control pregnancies (P < 0.001). Circulating concentrations of activin A also increased significantly in both the spontaneous and donor egg pregnancies (P < 0.001) during the study period. However, the concentrations of inhibin A and activin A in the first trimester of human pregnancy were not significantly different in the women with or without corpora lutea, suggesting a fetoplacental origin. Multiple donor egg pregnancies were found to have higher concentrations of inhibin A (P < 0.001) and activin A (P < 0.05) compared with singleton donor egg pregnancies, which also supports a placental source.

Background: Women with polycystic ovaries have associated risk factors for coronary artery disease. It is unknown whether women with more extensive coronary artery disease are more likely to have polycystic ovaries., Objective: To determine whether women who have more extensive coronary artery disease as seen on coronary angiography are more likely to have polycystic ovaries appearing on ultrasonography than are women with less severe coronary disease., Design: Prevalence study of women who had had coronary angiography., Setting: Women referred for coronary angiography for assessment of chest pain or valvular disease in Auckland, New Zealand, during a 2-year period., Patients: 143 women 60 years of age or younger who had had coronary angiography. Women who had previously had bilateral oophorectomy were excluded., Measurements: The extent of coronary artery disease assessed by quantitative angiography was compared with the presence or absence of polycystic ovaries. Pelvic ultrasonography was done without knowledge of the extent of coronary artery disease. Assessment of angiograms was blinded. Insulin resistance and gonadotropin, testosterone, and serum lipid levels were also measured., Results: Polycystic ovaries were found in 42% of women and were associated with hirsutism; previous hysterectomy; higher free testosterone, triglyceride, and C-peptide levels; and lower high-density lipoprotein cholesterol levels. Women with polycystic ovaries had more extensive coronary artery disease than women with normal ovaries (number of segments with > 50% stenosis, 1.7 [95% CI, 1.1 to 2.3] compared with 0.82 [CI, 0.54 to 1.1]; P < 0.01). On logistic regression analysis, the extent of coronary artery disease (P = 0.032) and family history of heart disease (P = 0.022) were predictors of the presence of polycystic ovaries., Conclusions: In women having coronary angiography, those with more extensive coronary artery disease were more likely to have polycystic ovaries on ultrasonography than were those with less extensive disease. Visualization of polycystic ovaries by sonography was associated with distinct metabolic and endocrine abnormalities. Further study is required to evaluate whether surgery or hormone replacement therapy can modify the risk.

Antiphospholipid antibodies have an established association with pregnancy complications such as recurrent miscarriage, growth retardation, placental abruption and stillbirth but their mechanism of action is unclear. We have investigated whether antiphospholipid antibodies occur more frequently in women having in-vitro fertilization (IVF) and whether their presence is associated with the likelihood of failed implantation. We studied 240 women undergoing IVF treatment who were

Objective: Polycystic ovaries have been diagnosed in more than 20% of premenopausal women using ultrasound. The aim of this study was to determine whether polycystic ovaries exist in post-menopausal women., Design: Two groups of women were studied; group 1 consisted of 18 post-menopausal volunteers and group 2 comprised 142 women, 94 of whom were post-menopausal who had recently undergone coronary angiography., Measurements: Transabdominal and transvaginal ultrasound scans were performed and measurements made of uterine area, endometrial thickness and ovarian volume. The morphological appearance of the ovaries was also noted. Fasting blood samples were taken. Medical and menstrual questionnaires were completed., Results: Polycystic ovaries were found in 8/18 (44%) of group 1 and 60/142 (42%) in group 2. Polycystic ovaries were detected in 35/94 (37%) of the post-menopausal women in group 2. Post-menopausal women with polycystic ovaries had larger ovaries containing more follicles compared with post-menopausal women with normal ovaries. Post-menopausal women with polycystic ovaries had higher serum concentrations of testosterone and triglycerides than had post-menopausal women with normal ovaries., Conclusions: Polycystic ovaries can be detected in post-menopausal women and have some of the same endocrine abnormalities which are evident in premenopausal women with polycystic ovaries, that is, raised serum concentrations of testosterone and triglycerides.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family. In rodents HB-EGF has been found to mediate the mitogenic effects of oestrogen on the endometrial glandular cells and those of progesterone on the stromal cells. HB-EGF has also been found to be expressed at the site of implantation before any other discernible sign of blastocyst attachment in rodents. Our aim was to determine whether HB-EGF mRNA was expressed in the human pregnant and non-pregnant endometrial tissues. Normal endometrial tissues at different stages of the menstrual cycle, first trimester chorionic villi and decidua, second trimester chorionic villi and term placental tissues were snap frozen and stored at -80 degrees C. Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyse the expression of HB-EGF mRNA in these tissues. HB-EGF mRNA was found to be expressed in human endometrium throughout the menstrual cycle. It was also present in first trimester chorionic villi and decidua, second trimester villi and term placenta. These findings suggest that HB-EGF may have a role in the growth or function of the human uterus, and that it may be important at the feto-maternal interface throughout pregnancy.

Polycystic ovaries (PCO) diagnosed by ultrasound have been commonly reported amongst healthy women. The study aimed to determine the prevalence of PCO in a population of women from the community, and to relate it to clinical and endocrinological data. Twelve hundred women chosen randomly from electoral rolls were invited to take part in the study. Two hundred and fifty five women (21%) who met eligibility criteria greed to participate and 183 women 916%) finally completed the study. Seventy two women did not attend. An ultrasound scan and blood tests were taken on day 5-9 of their menstrual cycles. Data about their menstrual periods and reproductive history was collected. The prevalence of PCO was 21% (39 of 183). No differences existed between women with PCO and normal ovaries with respect to uterine size, body mass index, luteinizing hormone levels, serum hormone binding globulin levels and fertility status. Hirsutism (Ferriman Gallwey score > 7), elevated testosterone levels and irregular menstrual cycles were significantly more frequent amongst women with PCO. Mean ovarian volume was larger in women with PCO irrespective of the use of hormonal contraception. Fifty nine per cent of women with PCO had irregular menstrual cycles or elevated Ferriman Gallwey scores or both. There was no detectable effect of PCO on parity or miscarriage although only 70% of women with PCO had evidence of an adequate ovulation compared to 95% of women with normal ovaries.

Antiphospholipid antibodies are a group of pathogenic antibodies associated with adverse pregnancy outcome. Pregnancies complicated by the presence of antibodies require careful surveillance and in specific situations therapy with low-dose aspirin, corticosteroids and/or heparin.

Erwinia carotovora and Pseudomonas aeruginosa secrete exoenzymes that contribute to the pathogenesis of plant and mammalian infections respectively. E.carotovora mutants defective in synthesis of the pectinase, cellulase and protease exoenzymes were isolated and classified into two groups. Group 2 mutants were found to be defective in the production of a small freely diffusible molecule, N-3-(oxohexanoyl)-L-homoserine, lactone (HSL), and were avirulent. Addition of exogenous HSL to these group 2 mutants restores synthesis of the exoenzymes and virulence in planta. Of the exoenzymes of P.aeruginosa the metalloprotease, elastase, is an established virulence determinant. Mutants of P.aeruginosa that are defective in elastase production have been isolated and were again found to fall into two groups. Analogous to the group 2 mutants of E.carotovora, group 2 mutants of P. aeruginosa are defective in the synthesis of HSL and exogenous HSL restores elastase production. HSL has now been linked to the control of bioluminescence in Vibrio fischeri, carbapenem antibiotic production of E.carotovora and the above exoenzyme virulence determinants. This information significantly enhances our understanding of the extent and nature of pheromone mediated gene expression control in prokaryotes.

We assessed the relationship between antiphospholipid antibodies and recurrent miscarriage, fetal deaths, and the pregnancy complications--placental abruption, fetal growth retardation and preeclampsia. The subjects were 81 women with a history of 3 or more miscarriages, 62 with a history of fetal death in the index pregnancy, 105 with a poor obstetric history or pregnancy complications and 13 with systemic lupus erythematosus. Antiphospholipid antibodies were found in 41% of women with a history of recurrent miscarriages, 29% with a history of recent intermediate fetal death or stillbirth, 19% with a poor obstetric history and 69% with systemic lupus erythematosus. There is a high incidence of antiphospholipid antibodies in complicated pregnancies. Patients presenting with the above pregnancy disorders should be tested for antiphospholipid antibodies because of the risk conferred on a fetus by their presence and to expand the treatment options.

Objective: to analyse all perinatal deaths at National Women's Hospital, Auckland, in a two year period, in order to identify areas in which changes could be made to improve the outcome for future pregnancies., Methods: an audit was performed of all perinatal deaths at National Women's Hospital, Auckland, in 1989 and 1990. All deaths were classified according to the primary obstetric factor which initiated the sequence of events leading to the death. The events surrounding each death were examined for the presence of avoidable factors., Results: there were 293 deaths after 20 weeks gestation, which included 172 fetal deaths, 116 neonatal deaths and five infant deaths. Fetal abnormality (24%) was the commonest cause of death followed by spontaneous prematurity (19%) and infection (11%). Fifty-one percent of the multigravid women who suffered a perinatal loss of a normally formed fetus had had a poor obstetric history. Avoidable factors were detected in 25% of all deaths., Conclusions: this audit clearly identified the causes of perinatal loss where improvements can be made. Advances in medical knowledge, technology and/or expertise are required to improve the outcome for the common causes of perinatal loss--fetal abnormality, prematurity and infection. Further staff and patient education with application of current knowledge and close attention to accepted standards of care should improve the outcome for the growth retarded fetus and the asphyxiated fetus in labour.