Predicting the chance of live birth for women undergoing IVF: a novel pretreatment counselling tool.

STUDY QUESTION: Which pretreatment patient variables have an effect on live birth rates following assisted conception? SUMMARY ANSWER: The predictors in the final multivariate logistic regression model found to be significantly associated with reduced chances of IVF/ICSI success were increasing age (particularly above 36 years), tubal factor infertility, unexplained infertility and Asian or Black ethnicity. WHAT IS KNOWN ALREADY: The two most widely recognized prediction models for live birth following IVF were developed on data from 1991 to 2007; pre-dating significant changes in clinical practice. These existing IVF outcome prediction models do not incorporate key pretreatment predictors, such as BMI, ethnicity and ovarian reserve, which are readily available now. STUDY DESIGN, SIZE, DURATION: In this cohort study a model to predict live birth was derived using data collected from 9915 women who underwent IVF/ICSI treatment at any CARE (Centres for Assisted Reproduction) clinic from 2008 to 2012. Model validation was performed on data collected from 2723 women who underwent treatment in 2013. The primary outcome for the model was live birth, which was defined as any birth event in which at least one baby was born alive and survived for more than 1 month. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 12 fertility clinics within the CARE consortium in the UK. Multivariable logistic regression was used to develop the model. Discriminatory ability was assessed using the area under receiver operating characteristic (AUROC) curve, and calibration was assessed using calibration-in-the-large and the calibration slope test. MAIN RESULTS AND THE ROLE OF CHANCE: The predictors in the final model were female age, BMI, ethnicity, antral follicle count (AFC), previous live birth, previous miscarriage, cause and duration of infertility. Upon assessing predictive ability, the AUROC curve for the final model and validation cohort was (0.62; 95% confidence interval (CI) 0.61-0.63) and (0.62; 95% CI 0.60-0.64) respectively. Calibration-in-the-large showed a systematic over-estimation of the predicted probability of live birth (Intercept (95% CI) = -0.168 (-0.252 to -0.084), P < 0.001). However, the calibration slope test was not significant (slope (95% CI) = 1.129 (0.893-1.365), P = 0.28). Due to the calibration-in-the-large test being significant we recalibrated the final model. The recalibrated model showed a much-improved calibration. LIMITATIONS, REASONS FOR CAUTION: Our model is unable to account for factors such as smoking and alcohol that can affect IVF/ICSI outcome and is somewhat restricted to representing the ethnic distribution and outcomes for the UK population only. We were unable to account for socioeconomic status and it may be that by having 75% of the population paying privately for their treatment, the results cannot be generalized to people of all socioeconomic backgrounds. In addition, patients and clinicians should understand this model is designed for use before treatment begins and does not include variables that become available (oocyte, embryo and endometrial) as treatment progresses. Finally, this model is also limited to use prior to first cycle only. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to present a novel, up-to-date model encompassing three readily available prognostic factors; female BMI, ovarian reserve and ethnicity, which have not previously been used in prediction models for IVF outcome. Following geographical validation, the model can be used to build a user-friendly interface to aid decision-making for couples and their clinicians. Thereafter, a feasibility study of its implementation could focus on patient acceptability and quality of decision-making. STUDY FUNDING/COMPETING INTEREST: None.

Integrating text mining into the MGI biocuration workflow.

A major challenge for functional and comparative genomics resource development is the extraction of data from the biomedical literature. Although text mining for biological data is an active research field, few applications have been integrated into production literature curation systems such as those of the model organism databases (MODs). Not only are most available biological natural language (bioNLP) and information retrieval and extraction solutions difficult to adapt to existing MOD curation workflows, but many also have high error rates or are unable to process documents available in those formats preferred by scientific journals.In September 2008, Mouse Genome Informatics (MGI) at The Jackson Laboratory initiated a search for dictionary-based text mining tools that we could integrate into our biocuration workflow. MGI has rigorous document triage and annotation procedures designed to identify appropriate articles about mouse genetics and genome biology. We currently screen approximately 1000 journal articles a month for Gene Ontology terms, gene mapping, gene expression, phenotype data and other key biological information. Although we do not foresee that curation tasks will ever be fully automated, we are eager to implement named entity recognition (NER) tools for gene tagging that can help streamline our curation workflow and simplify gene indexing tasks within the MGI system. Gene indexing is an MGI-specific curation function that involves identifying which mouse genes are being studied in an article, then associating the appropriate gene symbols with the article reference number in the MGI database.Here, we discuss our search process, performance metrics and success criteria, and how we identified a short list of potential text mining tools for further evaluation. We provide an overview of our pilot projects with NCBO's Open Biomedical Annotator and Fraunhofer SCAI's ProMiner. In doing so, we prove the potential for the further incorporation of semi-automated processes into the curation of the biomedical literature.

Fertility preservation of boys undergoing anti-cancer therapy: a review of the existing situation and prospects for the future.

With the advancement of medical science, most cancers in children are now treatable, the cure rate being almost 85%. In boys, one side effect of treatment (chemotherapy and radiotherapy) is destruction of the sperm precursor cells in the testis, resulting in the failure of sperm formation after puberty, and consequent infertility. At the time of anti-cancer treatment, future fertility of the boy patient is at the very bottom of the relative quality of life (RQL) parameters list; however, in adults infertility is an important issue following cure from cancer. In this article we have first reviewed the existing situation with regard to the state of the art of fertility preservation in young boys with cancer, and have then raised clinical and ethical issues and suggested a way forward. The review concludes with the emphasis that certain important issues still need to be resolved and, until these are, then the different techniques available should be confined to approved, ethical clinical trials where efficacy and safety can be fully evaluated.

Can we justify spermatid microinjection for severe male factor infertility?

During 1995 and 1996 the first spermatid pregnancies were announced with both round spermatid (ROSI) and elongated spermatid (ELSI) injections. These publications were flanked by live births from ROSI in a number of animal species, with resulting offspring appearing normal, healthy and fertile. However, the live births in humans heralded a scientific and ethical debate on the clinical use of this technology; and in a number of countries nationwide moratoria prohibiting spermatid microinjection were enjoined. Concerns surrounded the biological condition of spermatids and clinical implications of utilizing an immature spermatozoon for conception. Nevertheless, case reports and a few scientific studies on human spermatid conception have been published in recent years, and further polemic on testicular histopathology and prognosis has ensued. This paper reviews the current arguments on the clinical use of ROSI and ELSI, and evaluates the biology of the main contributory components of a spermatozoon to the subsequent embryo, namely the genetic material, the microtubular organizing complex and the putative oocyte activating factor. We also consider the relevant testicular histopathology and likely outcome in the context of the current birth rate from ROSI and ICSI. We conclude by considering the way forward for infertile men who require this technology to become genetic fathers, and whether the time is now appropriate to consider clinical trials.

Isolation, purification and assessment of viability of spermatogenic cells from testicular biopsies of azoospermic men.

The success of spermatid microinjection has generated many concerns. In particular, there is a lack of appropriate methodology for the isolation of large homogeneous populations of spermatids, with minimum loss of viability, from the testicular tissue of azoospermic men. Here we have compared two different isolation methods -- velocity sedimentation under unit gravity (VSUG) combined with discontinuous Percoll centrifugation (DPC), and separation with fluorescent-activated cell sorter (FACS) using light in the visible range -- to determine the most suitable method for the isolation of spermatids. Total mixed cell count/gram of testicular parenchyma was significantly higher in obstructive azoospermic men compared with non-obstructive azoospermic men (P < 0.001). The results of the comparison showed that in obstructive azoospermic patients the difference in the yields of primary spermatocytes produced by the two techniques was not significant, but for round and elongating spermatids the FACS separation proved to be the better method (P < 0.001). Similarly, in non-obstructive azoospermic patients, FACS separation proved to be superior, giving increased yields of primary spermatocytes and round and elongating spermatids compared with VSUG combined with DPC method (P < 0.001). More than 99 % of the separated cells retained their viability after FACS separation. As large homogeneous populations of viable spermatids can be separated with FACS in a relatively short period of time, FACS separation is the most suitable method for the isolation of spermatids from testicular biopsy tissue.

Severe ovarian hyperstimulation syndrome: is it really preventable by prophylactic intravenous albumin?

OBJECTIVE: To evaluate the effectiveness of i.v. albumin in preventing severe ovarian hyperstimulation syndrome (OHSS) in patients at risk. DESIGN: Retrospective review and data analysis. SETTING: University-based tertiary referral center for assisted reproductive technologies (ART). PATIENT(S): Sixty women at high risk of developing severe OHSS after superovulation for ART. INTERVENTION(S): One liter of albumin (4.5%) administered i.v. during oocyte retrieval and immediately afterward. RESULT(S): Of the 60 women who had prophylactic i.v. albumin, 5 (8%) developed severe OHSS, which led to hospitalization. Eight (13%) developed moderate OHSS. Forty-seven (78%) did not develop any symptoms. Four of the 5 women who developed severe OHSS had ET and 3 of them (75%) were pregnant (1 twin and 2 singletons). CONCLUSION(S): Intravenous albumin administered at oocyte retrieval does not prevent the occurrence of severe OHSS, especially in cases associated with pregnancy. It is important that clinicians are not lured into a false sense of security by the early report, full of promise, on the use of i.v. albumin to prevent severe OHSS.

'Curing' empty follicle syndrome.

We report a novel method of rescuing empty follicle syndrome (EFS) and provide evidence that it is a drug-related problem rather than a clinical dysfunction. In a preliminary study we established that in EFS the serum beta-human chorionic gonadotrophin (beta-HCG) concentrations 36 h after HCG administration never exceeded 10 mIU/ ml. beta-HCG concentrations were thus used to confirm EFS when oocytes were not retrieved from one ovary after controlled ovarian hyperstimulation. The procedure was suspended leaving intact all follicles in the second, ovary. After confirmation of EFS, a second HCG from a different batch was administered and 36 h later mature oocytes were retrieved from the intact ovary, suggesting a fault with the HCG previously administered. Three patients have been treated in this way. In the first case, four out of five mature eggs were fertilized after intracytoplasmic sperm injection (ICSI) resulting in the transfer of three top grade (grade 1) embryos. In the second case all seven mature oocytes fertilized after in-vitro fertilization (IVF) and three grade 1 embryos were transferred resulting in a twin pregnancy, now delivered. In the third case, five out of nine oocytes were fertilized after ICSI and one out of the three treated with high insemination concentration IVF fertilized, resulting in the transfer of three ICSI embryos.

Predicting empty follicle syndrome.

OBJECTIVE: To determine a simple predictive test for empty follicle syndrome before oocyte retrieval. DESIGN: Retrospective correlation analysis. SETTING: Patients attending Nottingham University Research and Treatment Unit, a tertiary, university-based assisted reproductive technologies (ART) program between April 1, 1994 and March 31, 1995. PATIENT(S): Six women in whom no oocytes were retrieved after superovulation for ART (empty follicle syndrome) were compared with 11 women with successful oocyte retrieval. INTERVENTION(S): Subcutaneous buserelin acetate plus IM hMG and hCG were used for superovulation. Oocyte retrieval was transvaginal and ultrasound guided. MAIN OUTCOME MEASURE(S): Ultrasound measurement of follicular growth and serum E2 levels during superovulation. Serum beta-hCG levels before and 36 hours after hCG administration IM. Number of oocytes retrieved. RESULT(S): Before hCG administration, beta-hCG was not detectable in the serum. The serum beta-hCG 36 hours after hCG was 209 +/- 16.7 mIU/mL (conversion factor to SI units, 1.0; mean +/- SEM, range 106 to 290 mIU/mL) in women with successful oocyte retrieval and 4 +/- 1.8 mIU/mL (range 0 to 9 mIU/mL) in empty follicle syndrome. This difference was significant. CONCLUSION(S): Empty follicle syndrome is associated with very low bioavailability of beta-hCG and can be predicted by measuring serum beta-hCG level 36 hours after IM hCG administration.

Computer image sperm selection as a novel approach to subzonal insemination in the human.

Utilizing real-time computer image analysis, individual spermatozoa were selected using microaspiration. Selection criteria were based on potential hyperactivation motility characteristics; the amplitude of lateral head displacement > 7.5 microns, curvilinear velocity > 70 microns/s and linearity of < 30%. For this pilot study, 16 patients (eight in each group) were recruited. Using subzonal insemination (SUZI), up to five (mean = 4.4 +/- 0.3) spermatozoa selected using computer-image sperm selection (CISS) were micro-injected, or up to 15 (mean = 12.8 +/- 1.3 SD) unselected spermatozoa. In the group which utilized CISS, 28 out of 49 (57%) oocytes were fertilized compared with 13 out of 52 (25%) utilizing conventional SUZI (P < 0.04); polyspermy was 20% (n = 10) and 2% (n = 1) respectively. CISS with SUZI showed increased efficiency in achieving fertilization and is a novel approach to studying individual sperm function in a sperm egg bioassay where gamete ratios are close to unity.

A positive correlation between expression of beta 1-integrin cell adhesion molecules and fertilizing ability of human spermatozoa in vitro.

The purpose of this study was to investigate firstly whether beta 1-integrin cell adhesion molecules are expressed by human spermatozoa, and secondly whether there is any relationship between the expression of beta 1-integrin cell adhesion molecules and the fertilizing ability of human spermatozoa in vitro. A total of 50 semen samples were examined. The samples were obtained from the male partners of couples undergoing in-vitro fertilization (IVF) for either unexplained, tubal or male factor infertility. A panel of six monoclonal antibodies against beta 1-integrin cell adhesion molecules and immunohistochemical techniques were used to identify the presence of these molecules on the spermatozoa. The percentage of spermatozoa showing strong immunolabelling with each monoclonal antibody was assessed in each sample. The relationship between these results and the aetiology of infertility and incidence of fertilization was examined. beta 1-Integrins, and primarily the ones with alpha 4-, alpha 5- and alpha 6-chains, were expressed by human spermatozoa. Compared with semen samples from unexplained or male factor infertility patients, samples from tubal infertility patients had a significantly higher (P < 0.05) percentage of spermatozoa expressing adhesion molecules. There was a positive correlation between the expression of alpha 4, alpha 5 and alpha 6 adhesion molecules and the fertilizing ability of spermatozoa. The positive correlation between the presence of certain beta 1-integrin cell adhesion molecules and the fertilizing ability of human spermatozoa suggests that integrins may be putative determinants in egg-sperm recognition and interaction.

Human sperm morphology evaluation pre- and post-Percoll gradient centrifugation.

Previous experiments have established a relationship between the morphological characteristics of human spermatozoa and their fertilizing potential in vitro. To assess further the efficiency of Percoll gradient centrifugation (PGC) as a method of sperm selection, we have examined morphological characteristics of spermatozoa from 86 teratozoospermic patients attending Nottingham University Research and Treatment Unit in Reproduction (NURTURE). Patients were divided into groups according to percentage normal morphology in the fresh sample: group A (n = 14), < 5% normal morphology; group B (n = 41), 5-14% normal morphology; and group C (n = 31), > 14% normal morphology. Morphology slides were prepared using Diff Quik staining techniques and evaluated by Kruger strict criteria, under oil immersion, at a magnification of x1000; specific defects, viz. head, neck, cytoplasmic droplets, tail, immature cells, were assessed individually. Following PGC, a sperm sample with enhanced morphology was recovered for group B (P < 0.01) and C (P < 0.005); however, for group A (very severe teratozoospermia) PGC did not select a sample with significantly improved morphological quality. Specific sperm defects affected by PGC were head, neck and immature cells. No significant difference was found for tail abnormalities or cytoplasmic fragments.

Intracytoplasmic sperm injection (ICSI) versus high insemination concentration (HIC) for human conception in vitro.

The use of high insemination concentration (HIC) for in vitro fertilization (IVF) was compared with intracytoplasmic sperm injection (ICSI) in cases of male factor infertility. Sibling oocytes (n = 252) from 24 patients were used, 123 for HIC and 129 for ICSI. Although the incidence of fertilization was decreased with HIC (48% v. 61%), this treatment was nevertheless a viable option for many patients, especially when ICSI was not available. However, there was a higher incidence of cytoplasmic fragmentation of embryos after HIC compared with ICSI (36% v. 10%, P = 0.003) and the outcome was significantly affected by the severity of teratozoospermia. Using a cut-off of 5% normal forms, the incidence of fertilization with HIC for the group with < 5% normal forms was 37% compared with 72% for the group with > 5% normal forms; there was also a significant decrease in cleavage rate (P = 0.05) and the number of regular embryos (P = 0.005), and an increase in cytoplasmic fragmentation (P = 0.006) in patients with < 5% normal forms. No distinction was made between cases of teratozoospermia when ICSI was used. The present study confirms the value of HIC as a first line treatment for male infertility, as long as ICSI remains significantly more expensive and concerns on safety are mooted. However, the use of sibling oocytes for ICSI is recommended, especially in cases with < 5% normal sperm morphology.

Subzonal insemination and zona breaching techniques for assisting conception in vitro.

The following comments can be made with regard to zona breaching procedures (PZD) and SUZI. First and foremost, it is important to establish that fertilization cannot occur with microdrop IVF or conventional IVF before proceeding with microassisted fertilization technology. PZD increases the rate of polyspermy, and this is significantly higher than when utilizing SUZI. SUZI increases the incidence of implantation in cases exhibiting severe teratozoospermia. SUZI increases the fertilization rate per patient and per oocyte in cases where IVF has previously failed on more than one occasion. SUZI increases the incidence of fertilization when very few motile sperm are available, and there is an increase in the incidence of cytoplasmic fragmentation with SUZI, which might be alleviated by improving methods of penetrating the zona pellucida, for example by using the Sonic Sword or utilizing a thinner, sharper injection needle alone or in addition to increasing the perivitelline space by dehydrating the oocyte (Yang et al, 1988). Morphology is an important parameter in predicting the outcome of IVF and therefore in guiding patients on the relevance of microinjection technology.

When are AIDS patients to blame for their disease? Effects of patients' sexual orientation and mode of transmission.

This study examined three factors affecting college students' attributions of blame for an AIDS patient's disease: sexual orientation of the patient, mode of HIV transmission, and the sex of the subject. 148 subjects read one of six vignettes describing an hypothetical AIDS patient who was described as either an heterosexual or an homosexual man who contracted HIV through one of three avenues: blood transfusion, sexual contact, or IV drug use. The homosexual AIDS patient was considered more to blame for his illness than the heterosexual AIDS patient, but only when mode of transmission was sexual contact. In addition, mode of HIV transmission was a significant factor in attributions of responsibility, as the patient who contracted HIV through a blood transfusion was rated as less responsible than the patient who contracted HIV through sexual behavior or IV drug use. Women consistently rated the AIDS patient as less responsible than did men.

Cortical magnetic resonance imaging changes in elderly inpatients with major depression.

OBJECTIVE: The purpose of the study was to determine if magnetic resonance imaging (MRI) scans of elderly depressed patients differ from MRI scans of age-matched control subjects and age-matched patients with Alzheimer's disease. METHOD: The authors studied 21 patients 60 years or older with major depression, 16 patients with Alzheimer's disease, and 14 age-matched control subjects. RESULTS: Compared to control subjects, depressed patients had greater cerebral sulcal and temporal sulcal atrophy; larger sylvian fissures, lateral ventricles, third ventricles, and temporal horns; and greater severity of subcortical white matter lesions. Depressed patients also had more basal ganglia lesions but similar levels of periventricular hyperintensity. There were no differences between depressed patients with and without delusions on any MRI measure. Depressed patients who received ECT had more temporal horn atrophy and greater subcortical abnormality summary scores than normal subjects. Cortical sulcal atrophy correlated with age at onset of depression. CONCLUSIONS: The findings suggest that elderly hospitalized depressed patients have greater cortical as well as subcortical atrophy and more basal ganglia lesions than age-matched normal control subjects. The correlation of these abnormalities with outcome remains unknown.

Systemic chemotherapy of advanced head and neck malignancies.

Several Phase II chemotherapy protocols were evaluated in patients with advanced malignancies; 158 were evaluable head and neck cases. The protocols were as follows: five-drug combination (COMFP), four-drug (COMF), (CCNU, Adriamycin, DTIC, and cytosine arabinoside. Insufficient numbers and data were received to adequately evaluate Yoshi 864, 5 Azacytidine, porfiromycin, BCNU, and Azaserine. Significant responses to therapy were noted in the four and five-drug combinations in which 30-44% of the patients had 50% or greater regression, with an average duration of 2.2 months. Adriamycin and CCNU demonstrated lesser antitumor effects, while DTIC and cytosine arabinoside did not demonstrate significant antitumor activity in the head and neck areas. Usual toxicity consisted largely of nausea and vomiting, leukopenia, and thrombocytopenia. Alopecia was not pronouced in Adriamycin-treated patients. It appears that combination chemotherapy had a higher response rate compared to single agents used in the different cooperative protocols.