Poor return on investment: investigating the barriers that cause low credentialing yields in a resource-limited clinical ultrasound training programme.

BACKGROUND: Clinical ultrasound is commonly used in medical practices worldwide due to the multiple benefits the modality offers clinicians. Rigorous credentialing standards are necessary to safeguard patients against operator errors. The purpose of the study was to establish and analyse the barriers that specifically lead to poor credentialing success within a resource-limited clinical ultrasound training programme. METHODS: An electronic cross-sectional survey was e-mailed to all trainees who attended the introductory clinical ultrasound courses held in Cape Town since its inception in 2009 to 2013. All trainees were followed until they completed their training programme in 2015. RESULTS: Only one fifth of trainees (n = 43, 19.7%), who entered the Cape Town training programme, credentialed successfully. Ninety (n = 90, 41.3%) trainees responded to the survey. Eighty-six (n = 86) surveys were included for analysis. Time constraints were the highest ranked barrier amongst all trainees. Access barriers (to trainers and ultrasound machines) were the second highest ranked amongst the non-credentialed group. A combination between access and logistical barriers (e.g. difficulty in finding patients with pathology to scan) were the second highest ranked in the credentialed group. CONCLUSIONS: Access barriers conspire to burden the Cape Town clinical ultrasound training programme. Novel solutions are necessary to overcome these access barriers to improve future credentialing success.

A complementary model for medical subspecialty training in South Africa.

The shortage of healthcare workers and doctors in the developing world compared with the developed world is problematic, and will continue to be so owing to the ongoing migration of qualified professionals and the inability of the state to remedy the shortfalls. This will seriously hamper the government's National Health Insurance plan and the sustainability of South Africa (SA)'s healthcare sector. Furthermore, it is well known that the duration of medical training in SA is exceptionally long, which discourages trainees. Medical corporates have taken a limited initiative to fund education projects in collaboration with academic institutions. These projects have been unstructured, mostly ad hoc, and poorly co-ordinated. The private corporate medical sector has expressed a desire to become involved on a much larger scale by means of more formalised structures. Given this background, the primary objective of our research was to develop a business model to complement the current academic medical subspecialty training.

Critical appraisal of conventional semen analysis in the context of varicocele.

Varicocele is present in approximately 15% of men, and, although it is the most commonly diagnosed cause of male infertility, nearly two-thirds of men with varicoceles remain fertile. It was decided to make use of the current evidence obtained from the previous meta-analyses between 2004 and 2015 as well as available articles covering this field, preferably randomized controlled articles dealing with the topic of semen analysis before and after repair. Two important meta-analyses were discussed as well as other articles dealing with the topic of semen analysis before and after varicocelectomy. The evidence suggests that all semen parameters improve after varicocele repair. Based on the available evidence, it is clear that there is a benefit in treating men with a palpable varicocele. One can expect that all semen parameters will improve within 3 months after repair.

Semen quality and prediction of IUI success in male subfertility: a systematic review.

Many variables may influence success rates after intrauterine insemination (IUI), including sperm quality in the native and washed semen sample. A literature search was performed to investigate the threshold levels of sperm parameters above which IUI pregnancy outcome is significantly improved and/or the cut-off values reaching substantial discriminative performance in an IUI programme. A search of MEDLINE, EMBASE and Cochrane Library revealed a total of 983 papers. Only 55 studies (5.6%) fulfilled the inclusion criteria and these papers were analysed. Sperm parameters most frequently examined were: (i) inseminating motile count after washing: cut-off value between 0.8 and 5 million; (ii) sperm morphology using strict criteria: cut-off value ⩾5% normal morphology; (iii) total motile sperm count in the native sperm sample: cut-off value of 5-10 million; and (iv) total motility in the native sperm sample: threshold value of 30%. The results indicate a lack of prospective studies, a lack of standardization in semen testing methodology and a huge heterogeneity of patient groups and IUI treatment strategies. More prospective cohort trials and prospective randomized trials investigating the predictive value of semen parameters on IUI outcome are urgently needed. It is generally believed that intrauterine insemination (IUI) with homologous semen should be a first-choice treatment to more invasive and expensive techniques of assisted reproduction in cases of cervical, unexplained and moderate male factor subfertility. The rationale for the use of artificial insemination is to increase gamete density at the site of fertilization. Scientific validation of this strategy is difficult because literature is rather confusing and inconclusive. Many variables may influence success rates after IUI treatment procedures. It seems logical that sperm quality has to be one of the main determinants to predict IUI success. Clinical practice would benefit from the establishment of threshold levels for sperm parameters above which IUI pregnancy outcome is significantly improved and below which a successful outcome is unlikely. We performed a literature search to investigate if such threshold levels are known. Most striking were the lack of standardization in semen-testing methodology and the huge heterogeneity of patient groups and IUI treatment strategies. The four sperm parameters most frequently examined were: (i) inseminating motile count after washing: cut-off value between 0.8 and 5 million; (ii) sperm morphology using strict criteria: cut-off value >4% normal morphology; (iii) total motile sperm count in native sperm sample: cut-off value of 5-10 million; and (iv) total motility in native sperm sample: threshold value of 30%. This review identified an urgent need for more and better prospective cohort trials investigating the predictive value of semen parameters on IUI pregnancy rate.

Mild ovarian stimulation for in vitro fertilization: are we ready to change? A meta-analysis.

OBJECTIVE: To compare the efficacy of mild ovarian stimulation versus conventional stimulation in in vitro fertilization (IVF). DESIGN: Meta-analysis. SEARCH STRATEGY: A systemic literature search was carried out for prospective randomised clinical trials. We electronically searched using PubMed, Medline and Embase for all the studies published from 1990 to December 2011. INTERVENTIONS: Mild ovarian stimulation IVF that uses lower doses and/or shorter duration of gonadotrophins in GnRH antagonist co-treated cycle compared with conventional stimulation IVF. MAIN OUTCOME MEASURES: Live birth rates per started cycle and ongoing pregnancy rates per started cycle of IVF. RESULTS: On live birth rate, there was a significant difference in favour of the conventional stimulation [70/444 (15.7%) mild vs. 78/325 (24%) conventional] (OR 0.59, CI 0.41-0.85, p = 0.004). Similar findings were observed in the ongoing pregnancy data [140/696 (20%) mild vs. 144/547 (26%) in favour of conventional stimulation] (OR 0.72, CI 0.55-0.93, p = 0.01). The sub-analysis of two studies showed a statistically significant reduction of hyperstimulation syndrome in favour of the mild stimulation (OR 0.27, CI 0.11-0.66). CONCLUSION: This analysis presents strong evidence in favour of conventional stimulation IVF, which therefore should currently be considered a treatment of choice for patients requiring IVF treatment.

The effect of the biochemical marker soluble human leukocyte antigen G on pregnancy outcome in assisted reproductive technology--a multicenter study.

OBJECTIVE: To determine whether the presence of soluble human leukocyte antigen G (sHLA-G) affects implantation and pregnancy outcomes in vitro. DESIGN: A multicenter retrospective study. SETTING: Six certified in vitro fertilization (IVF) units. PATIENT(S): Embryos obtained from 2,040 patients from six different IVF clinics. INTERVENTION(S): Soluble HLA-G determination on day-2 embryos after intracytoplasmic sperm injection, with embryos transferred on day 3 using the sHLA-G data. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (10- to 12-week ultrasound finding). RESULT(S): All embryos were individually cultured, and a chemiluminescence enzyme-linked immunosorbent assay was used to detect the presence of sHLA-G in the culture medium surrounding the embryos. Embryos were selected based on a positive sHLA-G result and a graduated embryo scoring (GES) score >70, or on embryo morphology if the test was negative. In all centers, a positive sHLA-G result was associated with an increase in the odds of an ongoing pregnancy. The incidence of an ongoing pregnancy was 2.52 times greater in embryos transferred on day 3 with a positive sHLA-G test result than the incidence of an ongoing pregnancy in embryos with a negative sHLA-G test result. CONCLUSION(S): Data from this multicenter study confirm that sHLA-G expression is a valuable noninvasive embryo marker to assist in improving pregnancy outcomes, with the theoretical potential to reduce multiple pregnancies.

The relationship between seminal leukocytes, oxidative status in the ejaculate, and apoptotic markers in human spermatozoa.

The aim of this study was to investigate the relationship between seminal leukocytes, reactive oxygen species (ROS) production in the ejaculate, and markers of apoptosis in human spermatozoa. Semen samples were collected from 60 patients attending fertility clinics at the Reproductive Biology Unit at Tygerberg Academic Hospital and Vincent Pallotti Hospital, Cape Town, South Africa. The concentration of seminal leukocytes was determined and was correlated with ROS production in the ejaculate, the percentage of superoxide (·O2(-))- and hydrogen peroxide (H2O2)-positive spermatozoa, glutathione activation in the ejaculate, and with markers of apoptosis in spermatozoa, namely cysteine-dependent aspartate-directed proteases (caspase)-3/7 activation, mitochondrial membrane potential (ΔΨm), and the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive sperm. Significant correlations with the concentration of seminal leukocytes were found for ROS production in the ejaculate, the percentage of ·O2(-)-positive spermatozoa, and caspase-3/7 activation in the ejaculate. Leukocytospermic samples showed significantly higher ROS production, percentage of ·O2(-)-positive sperm, GSH activation, and caspase-3/7 activation compared to non-leukocytospermic samples. The percentage of ·O2(-)-positive sperm was significantly correlated with sperm ΔΨm and caspase-3/7 activation in the ejaculate. Sperm ΔΨm and TUNEL-positive sperm did not correlate with seminal leukocyte concentration. Data demonstrate that high seminal leukocyte concentrations that leads to increased seminal ROS production, and is also associated with caspase activation in the male germ cell and increased mitochondrial ROS production. The latter could possibly be a result of disturbed ΔΨm. The activation of caspase-3/7 could then follow the increased intrinsic superoxide levels due to depleted intrinsic glutathione (GSH). These cellular events might not directly and immediately lead to DNA fragmentation as an endpoint of apoptosis because of topological hindrances.

A linear karyotypic association between PB-I, PB-II and blastomere using sequentially performed comparative genome hybridization with no association established between karyotype, morphologic, biochemical (sHLA-G expression) characteristics, blastocyst formation and subsequent pregnancy outcome.

BACKGROUND: The importance of oocyte/embryo ploidy to achieve implantation and a subsequent pregnancy. AIM: To correlate first and second polar bodies and day-3 blastomere ploidy, embryo morphology and biochemical (sHLA-G) characteristics with blastocyst development and in vitro pregnancy outcome. MATERIALS AND METHODS: All oocytes/zygotes and embryos were individually cultured to the blastocyst stage. PB-I, PB-II and blastomeres underwent complete karyotyping and sHLA-G expression was measured on day 2. RESULTS: 57 mature (MII) donor oocytes were obtained, 33/57 (57.9%) were aneuploid, 21/57 (36.8%) were euploid, and 3/57 (5%) were 'inconclusive'. No correlation was found between comparative genomic hybridization (CGH) status of PB-I, PB-II and the graduated embryo score. Furthermore, no correlation was established between PB-I CGH results and blastocyst morphology grade. There was a significant correlation between PB-I CGH and blastomere CGH results. Euploid and aneuploid PB-I developed into 58 and 67% blastocysts, respectively. ĸ statistics (>0.7) revealed a positive correlation between the ploidy of PB-I, PB-II and the blastomeres. CONCLUSION: Following ICSI and sequential genetic karyotyping of the oocyte/zygote and subsequent blastomeres, the majority of oocytes fertilized and subsequent zygotes developed into blastocysts, despite their ploidy status. We therefore conclude that blastocyst development is not associated with ploidy.

Assisted reproductive technology in South Africa: first results generated from the South African Register of Assisted Reproductive Techniques.

OBJECTIVE: We present the first report from the South African Register of Assisted Reproductive Techniques. METHODS: All assisted reproductive technology (ART) centres in South Africa were invited to join the register. Participant centres voluntarily submitted information from 2009 on the number of ART cycles, embryo transfers, clinical pregnancies, age of female partners or egg donors, and use of fertilisation techniques. Data were anonymised, pooled and analysed. RESULTS: The 12 participating units conducted a total of 4 512 oocyte aspirations and 3 872 embryo transfers in 2009, resulting in 1 303 clinical pregnancies. The clinical pregnancy rate (CPR) per aspiration and per embryo transfer was 28.9% and 33.6%, respectively. Fertilisation was achieved by intracytoplasmic sperm injection in two-thirds of cycles. In most cycles, 1 - 2 embryos or blastocysts were transferred. Female age was inversely related to pregnancy rate. CONCLUSION: The register achieved a high rate of participation. The reported number of ART cycles covers approximately 6% of the estimated ART demand in South Africa. The achieved CPRs compare favourably with those reported for other countries.

Association between clomiphene citrate and visual disturbances with special emphasis on central retinal vein occlusion: a review.

OBJECTIVES: To determine whether clomiphene citrate (CC) can be implicated as a cause for central retinal vein occlusion (CRVO) and other visual disturbances. METHODS: For this systematic review, we performed a search of the following databases: PubMed (1976 to November 2009), Medline Plus 2009, Cochrane Library (1996 to November 2009), Google and Google Scholar (1996 to November 2009). Thirty-five relevant titles (25 full papers and 10 abstracts) were identified and read by authors. No review has been published in the literature. The publications included describe adverse effects with clomid and selective estrogen receptor modulators and in particular visual disturbances. The population consisted of infertility patients under ovulation induction with CC. The main outcome measures were loss of vision due to CRVO and other visual changes. RESULTS: CC may predispose to CRVO, but further trials are clearly needed in this area. CONCLUSION: Physicians should be aware of the potential risk of CC, especially in patients with associated risk factors for CRVO. If visual disturbances occur, therapy should be terminated and the patient referred for specialist ophthalmic care.

Semenology training programs: 8 years' experience.

OBJECTIVE: To evaluate the immediate effect of hands-on training on the quality of technical skills of laboratory technicians. DESIGN: Retrospective analytical study. SETTING: Academic institutions and private infertility clinics. PARTICIPANTS: One hundred and ten laboratory technicians. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): First, 110 participants from 16 African countries attended 5-day semenology workshops at Tygerberg Hospital. During these workshops the methodology as described by the World Health Organization manual for the analysis of human semen, namely, sperm concentration, motility, vitality, and morphology, formed part of the curriculum. Second, two experienced morphology readers from the Tygerberg group presented 23 1-day sperm morphology workshops in nine other countries. RESULT(S): The semenology workshops indicated a significant improvement in the evaluation of sperm concentration only, whereas pretraining and posttraining results for motility did not differ. Vitality reports did not differ from those of the experienced worker in the first place. Calculation by means of a linear regression model showed a significant decrease in the mean posttraining scores from the pretraining scores for the sperm morphology courses. CONCLUSION(S): Training improved technical skills for the evaluation of morphology and sperm concentration. The evaluation of graded sperm motility seems to be more difficult to teach over a short period.

Embryo selection criteria based on morphology VERSUS the expression of a biochemical marker (sHLA-G) and a graduated embryo score: prediction of pregnancy outcome.

PURPOSE: To compare pregnancy and implantation rates when embryos are selected based on a single Day 3 (D 3) morphology score vs. a GES score plus sHLA-G expression. METHODS: A prospective randomized study (n = 214) undergoing fresh ICSI cycles. Embryos were selected for transfer based on either Day 3 morphology score (Group A) or GES-scoring plus sHLA-G expression (Group B). RESULTS: Clinical [35/107 (33%) vs. 52/107 (49%)] and ongoing pregnancy [20/107 (19%) vs. 52/107 (49%)] rates were significantly different between Group A and Group B (p < 0.05). Implantation rates were not significantly different between Group A [52/353 (15%)] and Group B [73/417 (18%)] (p < 0.05). The number of pregnancies lost during the first trimester was nearly 12 times higher in Group A [25/52 (48%)]. CONCLUSION: The miscarriage rate was significantly lower in Group B than Group A and the pregnancy results were superior when embryos were selected based on GES plus sHLA-G expression.

World Health Organization reference values for human semen characteristics.

BACKGROUND: Semen quality is taken as a surrogate measure of male fecundity in clinical andrology, male fertility, reproductive toxicology, epidemiology and pregnancy risk assessments. Reference intervals for values of semen parameters from a fertile population could provide data from which prognosis of fertility or diagnosis of infertility can be extrapolated. METHODS: Semen samples from over 4500 men in 14 countries on four continents were obtained from retrospective and prospective analyses on fertile men, men of unknown fertility status and men selected as normozoospermic. Men whose partners had a time-to-pregnancy (TTP) of < or =12 months were chosen as individuals to provide reference distributions for semen parameters. Distributions were also generated for a population assumed to represent the general population. RESULTS: The following one-sided lower reference limits, the fifth centiles (with 95th percent confidence intervals), were generated from men whose partners had TTP < or = 12 months: semen volume, 1.5 ml (1.4-1.7); total sperm number, 39 million per ejaculate (33-46); sperm concentration, 15 million per ml (12-16); vitality, 58% live (55-63); progressive motility, 32% (31-34); total (progressive + non-progressive) motility, 40% (38-42); morphologically normal forms, 4.0% (3.0-4.0). Semen quality of the reference population was superior to that of the men from the general population and normozoospermic men. CONCLUSIONS: The data represent sound reference distributions of semen characteristics of fertile men in a number of countries. They provide an appropriate tool in conjunction with clinical data to evaluate a patient's semen quality and prospects for fertility.

Selectivity of hyaluronic acid binding for spermatozoa with normal Tygerberg strict morphology.

During spermiogenesis, a plasma membrane remodelling step facilitates formation of sperm zona pellucida and hyaluronic acid (HA) binding sites. Enrichment of Tygerberg normal spermatozoa in HA-bound versus semen sperm fractions was postulated. Semen was placed on the uncoated A side and HA-coated B side of a semen chamber. After 15 min, the HA binding score (proportion of HA-bound motile spermatozoa) was assessed on the B side, and unbound spermatozoa were removed by gentle rinsing. Following Diff-Quick staining, sperm morphology of A and B sides was evaluated by three blinded investigators at Yale and Tygerberg. The proportion of Tygerberg normal spermatozoa was higher in HA-bound versus semen spermatozoa (n = 63 subjects) with a 3.04-fold improvement (95% confidence limits: 1.9-4.7) in 37 teratozoospermic men, comparable with a 4.2-fold enrichment in zona pellucida-bound spermatozoa reported earlier by the Tygerberg group. The morphology scores of three investigators were different but related, indicating that the variations reflect individual-to-individual differences in the perception of shape normality. The selection power of HA and zona pellucida for normal spermatozoa are similar. The sperm biomarkers of creatine phosphokinase (reflecting retained cytoplasm in arrested maturity spermatozoa) and chaperone protein HspA2 (heat shock protein) were proportional with sperm HA binding. As HA binding reflects sperm maturity and function, the combination of Tygerberg morphology and HA binding is likely to improve male infertility management.

Semen profiles of male partners in females presenting with endometriosis-associated subfertility.

OBJECTIVE: To establish fertile and subfertile groups of males in couples presenting with endometriosis-related infertility in the female. DESIGN: Retrospective study of semen profiles on partners of women undergoing surgery for endometriosis-related infertility. SETTING: University-affiliated assisted reproduction center. PATIENT(S): One hundred seventeen partners of females undergoing surgery for endometriosis related infertility. MAIN OUTCOME MEASURE(S): Fertility potential according to Tygerberg strict criteria for sperm evaluation. RESULT(S): A total of 65.8% of the semen analysis were reported normal according to the Tygerberg strict criteria and 34.2% were reported subfertile. Of the total, 11.96% of the patients studied had a severe defect (azoospermia, double, and triple defects). CONCLUSION(S): Labeling of the male in couples presenting with infertility as fertile, subfertile, or infertile plays an important role in decision making regarding management of the female presenting with endometriosis-related infertility. It is important that in future studies on the effect of surgery on improving pregnancy outcome in patients with endometriosis the semen profile be reported and thresholds used should be mentioned. This will contribute significantly to the future comparison of data on the impact of the male factors in couples presenting with endometriosis-related infertility.

Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review.

OBJECTIVE: The aim of this literature search is to establish if metformin is efficacious when given to clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) patients. DESIGN: Medline database was searched from 1 January 1980 to 1 January 2005. Inclusion criteria were prospective randomized control trials where metformin was randomized either with placebo or CC to induce ovulation in the CC-resistant patient. RESULT(S): Group 1: Four trials were prospective double-blind placebo controlled. When the data of the four trials were pooled, the overall effect of the addition of metformin in the CC patient was P=.0006 with a 95% confidence interval (CI) of odds ratio (OR) 1.81-8.84. Group 2: In two trials the randomization was only prospective. When the data of these two trials were pooled, the overall effect of the addition of metformin in the CC-resistant patient was P<.0001 with a 95% CI of OR 6.24-70.27. Groups 1 and 2: The combined data show an overall effect of P<.0001 with a 95% CI of OR 3.59-12.96. CONCLUSION(S): The addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction.

Use of a zona laser treatment system in assisted hatching: optimal laser utilization parameters.

OBJECTIVE: This study aimed to establish the benefit of laser micromanipulation of the zona pellucida as a method of assisted hatching and to determine the optimal technical settings. DESIGN: Prospective pilot study. SETTING: University teaching hospital. ANIMAL(S): Six- to 8-week-old F1 female mice. INTERVENTION(S): Mouse embryos were treated with a laser (Hamilton Thorne Research) using both research and preset clinical settings. The research option allows the user to alter pulse duration, number of pulses, and beam intensity. In this study, laser intensity and duration, as well as the depth and number of disruptions, were altered. MAIN OUTCOME MEASURE(S): Embryos were scored after treatment as either arrested blastocysts, arrested during hatching, hatched, or degenerate. RESULT(S): The treatment where the laser intensity was halved but the number of laser pulses used was doubled was the most beneficial treatment. Zona thinning was not effective. CONCLUSION(S): The study showed that laser-assisted hatching can safely and significantly increase the percentage of embryos reaching the hatched blastocyst stage. A proportionately sized hole in a human embryo may have the same beneficial effect as has been shown in this study.