Survival Dynamics in Advanced Ovarian Cancer: R2 Resection Versus No-Surgery Paths Explored.

BACKGROUND: Cytoreductive surgery is critical for optimal tumor clearance in advanced epithelial ovarian cancer (EOC). Despite best efforts, some patients may experience R2 (>1 cm) resection, while others may not undergo surgery at all. We aimed to compare outcomes between advanced EOC patients undergoing R2 resection and those who had no surgery. METHODS: Retrospective data from 51 patients with R2 resection were compared to 122 patients with no surgery between January 2015 and December 2019 at a UK tertiary referral centre. Progression-free survival (PFS) and overall survival (OS) were the study endpoints. Principal Component Analysis and Term Frequency - Inverse Document Frequency scores were utilized for data discrimination and prediction of R>2 cm from computed tomography pre-operative reports, respectively. RESULTS: No statistical significance was observed, except for age (73 vs 67 years in the no- surgery vs R2 group, P: .001). Principal Components explained 34% of data variances. Reasons for no surgery included age, co-morbidities, patient preference, refractory disease, patient deterioration or disease progression, and absence of measurable intra- abdominal disease). The median PFS and OS were 12 and 14 months for no-surgery, vs 14 and 26 months for R2 (P: .138 and P: .001, respectively). Serous histology and performance status independently predicted PFS in both no-surgery and R2 cohorts. In the no-surgery cohort, serous histology independently predicted OS, while in the R2 cohorts, both serous histology and adjuvant chemotherapy were independent prognostic features for OS. The bi-grams "abdominopelvic ascites" and "solid omental" were amongst those best discriminating between R>2 cm and R1-2 cm. CONCLUSIONS: R2 resection and no-surgery cohorts displayed unfavourable prognosis with a notable degree of uniformity. When cytoreduction results in suboptimal results, the survival benefit may still be higher compared to those who underwent no surgery.

The study examined outcomes in advanced epithelial ovarian cancer (EOC) patients who underwent either R2 (suboptimal) surgical resection or received no surgery at all at a UK tertiary referral center. Sophisticated machine learning methodolgies were used to analyze data patterns and predict the extent of resection (>2 cm) from pre-operative CT reports. Reasons for not undergoing surgery included older age, presence of other medical conditions, patient preference, progressive disease, patient decline, or lack of detectable intra-abdominal disease. Factors like serous histology and performance status iinfluenced the risk of recurrence in both groups, while serous histology and adjuvant chemotherapy predicted the risk of death in the R2 group. Word sequences like "omental disease" and "reduced bulk" helped differentiate between R>2 cm and less extensive resections (R1-2 cm). In summary, both R2 resection and no-surgery groups had poor outcomes, but patients who underwent R2 resection generally had better survival compared to those who received no surgery, even when complete tumor removal was not achieved.

Management of osteogenesis imperfecta type I in pregnancy; a review of literature applied to clinical practice.

PURPOSE: Osteogenesis imperfecta (OI) is a rare heritable heterogenous disorder characterized by bone fragility and susceptibility to fractures with a wide spectrum of clinical expression due to defects in collagen type I biosynthesis. The purpose of the review is to highlight the practical norms in pregnancies with osteogenesis imperfecta. METHODS: We carried out a literature review in MEDLINE on OI during pregnancy, focusing on diagnosis, therapy and delivery. We reviewed 28 articles (case reports, original articles and reviews). RESULTS: Pregnant women affected by type I OI should be closely monitored to assess fetal well-being and detect pregnancy-related complications associated with an increased risk for osteoporosis, restrictive pulmonary disease, cephalopelvic disproportion and other problems related to connective tissue disorders. Mode of delivery remains controversial and should be determined on an individual basis. CONCLUSION: In conclusion, women affected by type I OI represent a subset of patients whose pregnancies should be considered high risk and warrant a multidisciplinary approach in a referral center.

Menstrual cycle length: a surrogate measure of reproductive health capable of improving the accuracy of biochemical/sonographical ovarian reserve test in estimating the reproductive chances of women referred to ART.

BACKGROUND: Aim of the study was to investigate whether menstrual cycle length may be considered as a surrogate measure of reproductive health, improving the accuracy of biochemical/sonographical ovarian reserve test in estimating the reproductive chances of women referred to ART. METHODS: A retrospective-observational-study in Padua' public tertiary level Centre was conducted. A total of 455 normo-ovulatory infertile women scheduled for their first fresh non-donor IVF/ICSI treatment. The mean menstrual cycle length (MCL) during the preceding 6 months was calculated by physicians on the basis of information contained in our electronic database (first day of menstrual cycle collected every month by telephonic communication by single patients). We evaluated the relations between MCL, ovarian response to stimulation protocol, oocytes fertilization ratio, ovarian sensitivity index (OSI) and pregnancy rate in different cohorts of patients according to the class of age and the estimated ovarian reserve. RESULTS: In women younger than 35 years, MCL over 31 days may be associated with an increased risk of OHSS and with a good OSI. In women older than 35 years, and particularly than 40 years, MCL shortening may be considered as a marker of ovarian aging and may be associated with poor ovarian response, low OSI and reduced fertilization rate. When AMH serum value is lower than 1.1 ng/ml in patients older than 40 years, MCL may help Clinicians discriminate real from expected poor responders. Considering the pool of normoresponders, MCL was not correlated with pregnancy rate while a positive association was found with patients' age. CONCLUSIONS: MCL diary is more predictive than chronological age in estimating ovarian biological age and response to COH and it is more predictive than AMH in discriminating expected from real poor responders. In women older than 35 years MCL shortening may be considered as a marker of ovarian aging while chronological age remains most accurate parameter in predicting pregnancy.

The Relationship between Alexithymia and Intolerance of Uncertainty in Anorexia Nervosa.

BACKGROUND: Alexithymia and intolerance of uncertainty (IU) are relevant factors in social and emotional processing abilities in anorexia nervosa (AN) eventually rendering emotional coping difficult. However, the link potentially existing in AN between IU and alexithymia has been so far understudied. SAMPLING AND METHODS: Sixty-one patients affected by AN and 59 healthy controls (HC) were enrolled and assessed for study purposes. All participants completed the following self-report questionnaires: Intolerance of Uncertainty Scale, State Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI) and Toronto Alexithymia Scale. RESULTS: IU and alexithymia were greater in patients with AN when compared to HC. Moreover, in both AN and HC groups, IU and alexithymia significantly correlated with each other as well as with anxiety (STAI score) and depression (BDI score). No correlations were found between alexithymia and age. Patients' duration of illness was negatively correlated with two alexithymia subscales. After adjusting for anxiety, depression, body mass index and duration of illness (for AN), the correlation between IU and alexithymia remained significant. CONCLUSIONS: In addition to confirming previous findings on marked levels of IU and alexithymia in AN, this study showed for the first time a correlation between IU and alexithymia in both AN and HC. Moreover, this result remained significant after controlling for a number of clinical variables. Taken together, these findings may have useful clinical implications for the treatment of AN sufferers. © 2015 S. Karger AG, Basel.

Acute immunomodulatory changes during controlled ovarian stimulation: evidence from the first trial investigating the short-term effects of estradiol on biomarkers and B cells involved in autoimmunity.

PURPOSE: The aim of the present study was to evaluate the in vivo immunomodulatory effects of an acute short-term estradiol (E(2)) increase on serum levels of B cell-activating factor (BAFF), immunoglobulins (Ig), anti-nuclear antibodies (ANA), and the peripheral B cell phenotype. METHODS: We conducted, at the Infertility Center of the University of Padua, a prospective case-control study on a cohort of infertile normo-responder women (group-A, 63 patients) undergoing controlled ovarian stimulation (COS) compared with an age-matched cohort of normo-ovulatory healthy women (group-B, 39 patients). Three serial blood sample assays were conducted in both groups, at T0, hypothalamic suppression; T1, ovulation induction; and T2, ßhCG test in group A, and at T0, 2nd day; T1, 14th day; and T2, 21st day of cycle in group B, and serum levels of E(2) and BAFF, BAFF/E(2) ratio, circulating IgM, IgG, and IgA, ANA titer, and peripheral B cell phenotype were measured. We compared group-A versus group-B in terms of absolute and E(2) normalized values of BAFF at baseline (T0) to verify for possible differences between healthy and infertile women, at T1 to verify for possible differences occurring after spontaneous ovulation versus COS, and at T2 to evaluate differences in serum BAFF levels between pregnant versus non-pregnant patients (considering only group-A) and between non-pregnant women after spontaneous versus COS cycles (group-B versus group-A). In group-A, we also evaluated IgM, IgG, IgA levels, ANA titer, and peripheral B cell phenotype at T0 versus T1 versus T2. RESULTS: With the exception of E(2) levels at T1 (as expected), no significant differences were found between the two groups for all outcome measures. In group-A, BAFF at T0 positively correlated with IgM levels; marginal zone CD19+/CD27+/IgD+ memory B cell compartment tended to be expanded at T1 when compared with T0. CONCLUSIONS: Despite several mechanistic and clinical studies supporting a stimulatory role of E(2) on autoimmunity, the acute increase of E(2) during COS for infertility treatment does not seem to have a major impact on the immune system.

Could surgeon's expertise resolve the debate about surgery effectiveness in treatment of endometriosis-related infertility?

PURPOSE: Restoring the anatomical relationship and preserving the function of pelvic organs represent the ideal outcome of surgical intervention in patients suffering from endometriosis-related infertility. The aim of the study was to compare two large cohorts (Group A and Group B) of infertile patients in terms of postsurgical spontaneous/assisted fertility and perioperative surgical outcomes. The surgical treatment was performed by a skilled surgeon (Group A) and a surgeon dedicated to endometriosis-related infertility (Group B). METHODS: An observational cohort study on women affected by pelvic endometriosis who underwent laparoscopic treatment (to restore/improve their fertility) was conducted. A comparison, between Group A and Group B, in terms of perioperative surgical outcomes, clinical/ongoing pregnancy and live birth rates, spontaneous pregnancy rate and obstetrical outcome was performed. RESULTS: A significantly higher spontaneous fertility rate (particularly in the first year after surgery) and lower ectopic pregnancy rate were found in Group B. ART success rates were not affected by different surgical approaches. Perioperative and obstetrical outcomes were similar in both groups. CONCLUSION: In patients affected by endometriosis, the choice between expectant management versus intervention should be personalized: when the estimated probability of natural conception is low, surgery may be considered as a second-line treatment. Conversely, in all other cases surgery should be offered early (as a first-line approach) as it improves the chance of spontaneous conception. The laparoscopic treatment of infertility due to endometriosis must be performed by a skilled specialized surgeon to ensure a complete "pelvic cleanout" while respecting the anatomical structures and reducing the risk of fertility impairment due to surgical procedures.

Subtotal versus total laparoscopic hysterectomy: could women sexual function recovery overcome the surgical outcomes in pre-operatory decision making?

PURPOSE: Hysterectomy is the most common surgical procedure performed in gynecology and, in over 95% of the cases, does not necessarily require the removal of the uterine cervix to be completed successfully. In clinical practice, however, less than 20% of gynecologists offer patients the possibility to express a personal preference concerning the choice between total laparoscopic hysterectomy (TLH) and laparoscopic subtotal hysterectomy (LSH). The aim of this study is to compare patients who have undergone TLH versus LSH for benign uterine diseases in terms of intra-operative/peri-operative surgical outcomes and short-term recovery of sexual function. METHODS: We performed an observational, retrospective study on 478 women who underwent hysterectomy for benign uterine disease at Gyn/Ob Clinic, Department of Women's and Children's Health of Padua University between January 2003 and December 2012. Surgical data were recorded. We investigated and compared outcomes between the two groups of patients (TLH vs LSH) in terms of the following: surgical complications rate, post-operative therapy, women satisfaction and sexual activity recovery. RESULTS: We found that operating time and length of hospital stay were significantly lower in patients who underwent LSH. A higher rate of post-operative fever was reported in the TLH treatment group although antibiotic prophylaxis was implemented in a similar fashion for both groups. At 60-70 days following surgery, women of LSH group reported a greater ease in recovery of sexual function as opposed to those who underwent TLH. CONCLUSIONS: The advantages and potential drawbacks of both procedures need to be discussed with women presenting with benign disease. LSH is a reasonable option for women, representing both an excellent minimally invasive approach in a proper clinical setting and an appropriate procedure for those women who prefer conservative surgery.

A new method to measure oxygen solubility in organic solvents through optical oxygen sensing.

A new method to measure oxygen concentration in air-saturated organic solvents and binary mixtures has been developed. The methodology relies on the ability of HPLC columns to retain the molecular oxygen contained in different types of solvents which are injected into the system at 298.15 K. The outlet of the HPLC is coupled with an optical oxygen sensor which continuously measures changes in oxygen partial pressure.

Enzyme-based online monitoring and measurement of antioxidant activity using an optical oxygen sensor coupled to an HPLC system.

It is estimated that up to 50% of the adult population take antioxidant products on a daily basis to promote their health status. Strangely, despite the well-recognized importance of antioxidants, currently there is no international standard index for labeling owing to the lack of standardized methods for antioxidant measurement in complex products. Here, an online high-performance liquid chromatography (HPLC)-based method to detect and measure the total antioxidant capacity of antioxidant samples is presented. In this approach, complex samples containing antioxidants are separated by the HPLC system, which is further coupled to an antioxidant measuring system consisting of an optical oxygen sensor, laccase, and tetramethoxy azobismethylene quinone (TMAMQ). The antioxidants, separated via HPLC, reduce TMAMQ to syringaldazine, which is then reoxidized by laccase while simultaneously consuming O(2). The amount of consumed oxygen is directly proportional to the concentration of antioxidants and is measured by the optical oxygen sensor. The sensor is fabricated by coating a glass capillary with an oxygen-sensitive thin layer made of platinum(II) meso-tetra(4-fluorophenyl)tetrabenzoporphyrin and polystyrene, which makes real-time analysis possible (t(90) = 1.1 s in solution). Four selected antioxidants (3 mM), namely, catechin, ferulic acid, naringenin (used as a control), and Trolox, representing flavonol, hydrocinnamic acid, flavanone, and vitamin E, respectively, were injected into the online antioxidant monitoring system, separated, and then mixed with the TMAMQ/laccase solution, which resulted in oxygen consumption. This study shows that, with the use of such a system, the antioxidant activity of individual antioxidant molecules in a sample and their contribution to the total antioxidant activity of the sample can be correctly assigned.

Incidental Finding of Thickened Endometrium in Postmenopausal Women: A Survey of Endometrial Cancer.

Objectives The primary objective was to determine the prevalence of endometrial cancer in asymptomatic and symptomatic postmenopausal women referred to the hysteroscopy service for incidental finding of thickened endometrium. The secondary objectives were to identify, for the asymptomatic cohort, an acceptable threshold of endometrial thickness (ET) which should trigger endometrial sampling and its related sensitivity and specificity. Methods This was a retrospective cohort study of 136 asymptomatic and 602 symptomatic postmenopausal women with an ET of >4 mm referred to the endometrial cancer diagnostic service in a gynecology oncology center over a period of one year. Clincal and demographic data were analyzed. Histopathological diagnosis was completed and receiver operating characteristic (ROC) curves for acceptable ET cutoff in asymptomatic women were evaluated. Results The prevalence of malignancy and atypical hyperplasia in asymptomatic women was 3.7% and 4.4%, respectively. Within the asymptomatic subgroup with ET <11 mm, the yield rate for atypical hyperplasia (AH)+cancer was 2.2%. An ET <10 mm gave a similar yield; however, specificity decreased. ET (t-test p-value=0.037) correlates with endometrial pathology. Receiver operating characteristic (ROC) curves identified a cutoff of 11 mm as an acceptable threshold for triggering further investigations. Conclusion Based on our findings, 11 mm may represent an acceptable threshold for further investigation in asymptomatic postmenopausal women. We strongly advocate qualitative assessment of the endometrium and evaluation of individual risk factors in women with ET between 4 mm and 11 mm. This study will contribute to the existing body of evidence for the management of asymptomatic postmenopausal women with incidental increased ET. Further studies are required.

Unusual inverse temperature dependence on reaction rate in the asymmetric autocatalytic alkylation of pyrimidyl aldehydes.

Observations of an intriguing inverse temperature dependence on reaction rate and a profound induction period in the Soai autocatalytic reaction are reported along with detailed kinetic and NMR investigations of the product alkoxide at low temperatures, leading to the suggestion that the active catalyst is derived in situ from the tetrameric ground state.

Surgery of Benign Ovarian Masses by a Gynecological Cancer Surgeon: A Cohort Study in a Tertiary Cancer Centre.

Objectives This study aimed to evaluate diagnostic performance in characterising ovarian masses by our gynaecological oncology multidisciplinary team meeting (MDM). Surgical outcome and overall impact on patients and healthcare service were also assessed. Methods This was a prospective cohort study of all women with adnexal masses presenting to the gynaecological oncology MDM at a central London tertiary cancer centre between February 2017 and February 2018. The multidisciplinary team (MDT) outcome, imaging details, subjective opinion, tumour markers, surgical details, and final histological diagnosis were collected. Diagnostic performance was also determined. Results There were 200 eligible patients in the study period. MDM imaging review demonstrated a sensitivity of 98.4% (95% CI: 94.3% to 99.8%) and a specificity of 52% (95% CI: 40.2% to 63.7%). Thirty-five cases were false positive, either presumed invasive cancers (51%) or borderline tumours (49%). The most common histological types were serous (37%) and mucinous (31%) cystadenomas. A retrospective application of the International Ovarian Tumor Analysis (IOTA) Assessment of Different NEoplasias in the adneXa (ADNEX) model suggests a potential reduction in false-positive rates (17%). Among the false-positive cases, there was no postoperative (90 days) mortality and postoperative morbidity was 14% with only grade 2 (CD2) complications according to Clavien and Dindo's CD classification. Conclusion An MDT has high sensitivity but low specificity when characterising ovarian masses referred with possible ovarian cancer to the tertiary centre. False-positive values in ovarian cancers are an important indicator of over-treatment. More research is required to assess other methods, such as the IOTA ADNEX model, to reduce the false-positive value.

A novel hysteroscopic approach for ovarian cancer screening/early diagnosis.

The lethality of epithelial ovarian cancer (EOC) may be due to common misconceptions regarding etiology and the absence of effective screening and early diagnostic tools. Reviews of histopathological surveys performed on the resected fallopian tubes of breast cancer (BRCA) mutation carriers, who underwent risk-reducing salpingo-oophorectomy, unexpectedly revealed the presence of occult carcinomas of the fallopian tubes. This finding prompted studies that demonstrated the most accredited theory of type II EOC development, which suggests that a large proportion of these tumors are derived from the fallopian tube. At present, no diagnostic tools or screening programs have been demonstrated to be effective or cost-effective in improving the outcome of EOC; it is therefore imperative that the scientific community unite its efforts in the identification of a valid screening and/or early diagnostic method for the treatment of this lethal gynecological malignancy. To this end, the present paper proposes a novel tool for the screening/early diagnosis of EOC: The 'Tuba-check'. This novel approach is based on the possibility of acquiring specimens for tubal lumen cytology via hysteroscopy in a minimally-invasive outpatient setting. The present study protocol aimed to validate the technical feasibility and oncological accuracy of the proposed approach, commencing with a cohort of patients with an expected increased oncological risk, including BRCA mutation carriers or those with a gene expression profile of 'BRCA-ness'. If the data collected by the present study protocol validates this approach, the 'Tuba-check' may, in the near future, be extended for the treatment of all women, therefore reducing the number of victims of epithelial ovarian carcinoma.

Eating Disorders, Autoimmune, and Autoinflammatory Disease.

OBJECTIVES: Identifying factors associated with risk for eating disorders is important for clarifying etiology and for enhancing early detection of eating disorders in primary care. We hypothesized that autoimmune and autoinflammatory diseases would be associated with eating disorders in children and adolescents and that family history of these illnesses would be associated with eating disorders in probands. METHODS: In this large, nationwide, population-based cohort study of all children and adolescents born in Denmark between 1989 and 2006 and managed until 2012, Danish medical registers captured all inpatient and outpatient diagnoses of eating disorders and autoimmune and autoinflammatory diseases. The study population included 930 977 individuals (48.7% girls). Cox proportional hazards regression models and logistic regression were applied to evaluate associations. RESULTS: We found significantly higher hazards of eating disorders for children and adolescents with autoimmune or autoinflammatory diseases: 36% higher hazard for anorexia nervosa, 73% for bulimia nervosa, and 72% for an eating disorder not otherwise specified. The association was particularly strong in boys. Parental autoimmune or autoinflammatory disease history was associated with significantly increased odds for anorexia nervosa (odds ratio [OR] = 1.13, confidence interval [CI] = 1.01-1.25), bulimia nervosa (OR = 1.29; CI = 1.08-1.55) and for an eating disorder not otherwise specified (OR = 1.27; CI = 1.13-1.44). CONCLUSIONS: Autoimmune and autoinflammatory diseases are associated with increased risk for eating disorders. Ultimately, understanding the role of immune system disturbance for the etiology and pathogenesis of eating disorders could point toward novel treatment targets.

Statins as Targeted "Magical Pills" for the Conservative Treatment of Endometriosis: May Potential Adverse Effects on Female Fertility Represent the "Dark Side of the Same Coin"? A Systematic Review of Literature.

The aim of the study was to analyze all the available evidence from both in vitro and in vivo studies regarding the efficacy of statin therapy in the treatment of endometriosis, evaluating the potential efficacy, side effects, and contraindications of their administration in humans. We focused on defining the potential benefits that the administration of statins may have on patients affected by endometriosis and the possible adverse effects of such a therapy on ovarian function and fertility profile. According to our article selection criteria, we included in the review in vitro and in vivo studies performed on human or animal models. The systematic review of literature identified 24 eligible articles, 12 of which reported evidence regarding the effects of statins on endometrial/endometriotic cells and 12 regarding their effects on ovarian function and fertility. All articles seem to emphasize the utility of statin administration in the treatment of endometriosis due to their anti-proliferative/proapoptotic effects, their ability to reduce cell viability and migration, and the inhibition of angiogenesis and anti-inflammatory activities. Regarding the potential adverse effects on gonadal activities, steroidogenesis and fertility function, no conclusive data were collected in human models (excluding women affected by polycystic ovary syndrome in which significant decline of androgen levels was reported after statin treatment), while contrasting results were reported by studies conducted in in vitro and in vivo in animal models. Despite evidence supporting statins as the potential therapeutic agent for a targeted conservative treatment of endometriosis, the uncertainties regarding their impact on gonadal function may not define them as an appropriate therapy for all young fertile women.

Preventive and Therapeutic Role of Dietary Inositol Supplementation in Periconceptional Period and During Pregnancy: A Summary of Evidences and Future Applications.

Although inositol dietary deficiency in the general population has not been demonstrated at the serum level, several findings are emerging regarding the impact of inositol supplementation in periconceptional period and in early phases of pregnancy. We are aimed to summarize all experimental (murine in vivo and in vitro murine embryo studies) and clinical (human) evidences regarding the role of inositol in the prevention and treatment of folate-resistant embryo neural tube defects (FR-NTDs) and gestational diabetes mellitus (GDM). We also collected all information regarding the effect that inositol supplementation may have in the metabolic reassessment of early and late pregnancy in order to draw evidence-based conclusions and suggest further studies defining the potential therapeutic role of this molecule in human reproduction. The systematic review of literature clearly showed that inositol supplementation in preconceptional period and in early phase of pregnancy reduces the risk of developing GDM in patients at increased risk. Furthermore, continued intake during pregnancy improves the metabolic status of affected patients, but further studies are needed to confirm this end point. All women at risk of FR-NTDs assuming inositol from the periconceptional period until late pregnancy are reported to have healthy newborns without any significant complications linked to inositol supplementation.

New frontiers in human assisted reproduction ­ from research to clinical practice: Several considerations (Review).

In the era of very late, or advanced, motherhood, in which 'egg banks', 'social' egg­freezing, egg donation and surrogacy represent a potential solution to a number of obstacles to human reproduction, what is the role of scientists and clinicians involved in assisted reproduction? In light of the apprehension that, in the future, through fertility treatment infertility may be passed on to the offspring, boundaries of medical vs. 'social' infertility are being created. Scientists and clinicians are joining forces in a synergistic effort to improve the effectiveness of infertility care by introducing novel therapeutic protocols with the intent of customising care and improving cost­effectiveness, testing novel drugs and formulations, and searching for novel markers (for estimating biological age) and nomograms (to optimise the yield of a controlled ovarian hyperstimulation cycle). On the other hand, political, social and health institutions are doing little to educate young women with respect to disinformation and to increase their awareness regarding age as the predominant factor that contributes towards the decline in fertility. Nevertheless, despite the great advances that have been made, 38 years after the birth of the first baby via in vitro fertilisation, the intricate road leading from the antral follicle to the fully developed baby continues to be designated as being too 'expensive', 'empirical', 'mysterious' or 'bound by ethics', with few significant improvements in terms of real cost­effectiveness.