[The relationship of mental health providers with health insurers; an exploration]. / De ggz in relatie tot zorgverzekeraars; een verkenning.

BACKGROUND: In 2020, Zorgverzekeraars Nederland (ZN), the umbrella organization of nine health insurers in The Netherlands. presented a vision of the future of mental health care in the Netherlands in ‘De GGZ in 2025. Vergezicht op de geestelijke gezondheidszorg’ (‘Outlook on mental health care’). This document can be seen as marking the fact that key stakeholders share a common vision on the future of the GGZ in the Netherlands. Contracting care is often difficult. The tension between providing quality and sufficient care and available funding leads to friction. Congruence in vision, goals and practices are important conditions for adequate relationship building. Does the vision document contribute to this? AIM: To discuss the experiences of mental health care administrators and health insurers in contracting and collaboration. METHOD: Conducting interviews with both directors of mental health institutions and the strategic (policy) advisors of health insurers. In the approach we used the salience model. RESULTS: The relationship between mental health care administrators and health insurers is perceived to be distrustful and complex, and has deteriorated slightly in 2021 compared to 2019. Perceived power, legitimacy and urgency affect the relationship. Almost all health insurers are characterized as dominant stakeholders based on the salience model. Both parties are open to improving the relationship, which requires more transparency and mutual understanding. CONCLUSION: With the supported content of the vision document, there is to some extent shared governance. The change steps (shared innovation) considered desirable will be promoted by partly granting the intended benefits to each other (shared savings).

Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial.

BACKGROUND: Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. METHODS: In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants. FINDINGS: 1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures. INTERPRETATION: Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned. FUNDING: Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Is home-based monitoring of ovulation to time frozen embryo transfer a cost-effective alternative for hospital-based monitoring of ovulation? Study protocol of the multicentre, non-inferiority Antarctica-2 randomised controlled trial.

STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman's point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN SIZE DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS SETTING METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTERESTS: The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017. DATE OF FIRST PATIENT'S ENROLMENT: 10 April 2018.

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH).

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.

Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study: a randomized controlled trial (NTR 5342).

BACKGROUND: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. METHOD: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12 months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. DISCUSSION: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. TRIAL REGISTRATION: NTR 5342 , registered July 31st, 2015. PROTOCOL VERSION: Version 4.10, January 4th, 2017.

Interactions of full-fat canola seed, oat hulls as an insoluble fiber source and pellet temperature for nutrient utilization and growth performance of broiler chickens.

The effectiveness of the addition of oat hulls (OH) as an insoluble fiber for improving nutrient digestibility and performance of birds fed diets containing full-fat canola seed (CS) was studied. A 2 × 2 × 2 factorial arrangement of treatments was used to assess the main effects of canola source (CS vs canola meal plus oil as control), OH (0 or 3%), pellet temperature (75 and 90°C) and their interactions. A total of 576 male day-old Ross 308 chickens were assigned to 8 experimental treatments, each replicated 6 times (12 birds per replicate). All birds were fed a same commercial starter diet for the first 10 d of age. Canola meal and canola oil in the control diets were replaced with CS at 11.6% and 13.5% in the grower (d 10 to 24) and finisher (d 24 to 35) diets, respectively. An interaction was observed between canola source and OH led to improved body weight gain (P < 0.01) and FCR (P < 0.05) in birds fed the combination of CS and OH in grower phase. Pelleting temperature at 75 vs 90°C did not affect performance of broilers. Birds fed diets containing OH had heavier gizzards at 24 and 35 d of age. Inclusion of CS in the diets depressed fat digestibility at d 24 (P < 0.001) and AME of the grower diets. At d 35, there was a significant interaction (P < 0.05) between CS and pellet temperature where birds fed CS diets pelleted at 75°C had higher fat digestibility than birds fed CS pelleted at 90°C. Regardless of canola source or pellet temperature, OH increased fat utilization at d 35 (P < 0.001) but had no effect on AME of the grower diets. In conclusion, CS can replace supplemental oil in broiler diets when an adequate source of insoluble fiber is included in the diet, which may help to maintain feed intake of broilers fed CS in steam-pelleted diets.

A new cinnamoylglycoflavonoid, antimycobacterial and antioxidant constituents from Heritiera littoralis leaf extracts.

A new cinnamolyglycoflavonoid 3-cinnamoyltribuloside (1), its precursor tribuloside and two known flavonoid glycosides afzelin and astilbin were isolated from Heritiera littoralis Dryand (Sterculiaceae) ethanolic leaf extract. The dichloromethane leaf extract afforded two known pentacyclic triterpenoids, 3ß-taraxerol and friedelin. Extracts and compounds isolated therefrom, with the exception of 3ß-taraxerol, exhibited antimycobacterial activity against the non-pathogenic Mycobacterium species Mycobacterium madagascariense and Mycobacterium indicus pranii, with a minimum inhibitory concentration (MIC) 5.0 mg/mL for the crude extracts and MICs in the range of 1.6-0.8 mg/mL for the pure compounds. The extracts together with 3-cinnamoyltribuloside (1), tribuloside and astilbin exhibited 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. The compounds that showed dual activities could be further evaluated under clinical settings for co-administration with standard anti-tuberculosis drugs.

Short communication: Effect of automatic postmilking teat disinfection and cluster flushing on the milking work routine.

The importance of a consistent and comprehensive milking routine as a critical component of any mastitis control program is well documented. However, as pressure on time increases, farmers are faced with 3 options: (1) adjust the milking routine to suit the time available, (2) undertake the task less thoroughly, or (3) examine which elements of the milking routine can be automated and substitute capital expenditure for labor. A study was undertaken on 5 farms in the United Kingdom in October and November 2007 to assess the effect on milking time of installing a commercial automatic postmilking teat disinfection and cluster back flushing system (ADF). Two of the farms recruited for the study were intending to purchase the ADF system in the near future and 3 farms had already invested in the technology. The farms ranged in size from 120 to 550 cows and included three 90° rapid exit parlors, a herringbone parlor, and an abreast parlor. All 5 farms were visited for 2 successive milkings before the ADF was installed or disabled, and a detailed time and motion analysis was undertaken. After ADF was installed or the system reactivated, a further 2 milkings were monitored. All monitored farms showed a measurable reduction in milking time after the ADF system was installed. However, the magnitude of the reduction was greater than would be expected by simply removing the elements of postmilking teat disinfection and cluster sanitization. The benefits of ADF are greater than simply disinfecting teats and back flushing clusters and the time saving obtained may allow a more structured milking routine that may have additional benefits in terms of mastitis prevention and control.

Psychological well-being and sexarche in women with polycystic ovary syndrome.

BACKGROUND: The characteristics of polycystic ovary syndrome (PCOS) such as hyperandrogenism and anovulation can be highly stressful and might negatively affect psychological well-being and sexuality. The objective of this study was to evaluate the association between PCOS characteristics and psychological well-being as well as sexarche. METHODS: Patients (n = 1148) underwent standardized clinical evaluation. Psychological well-being was investigated in 480 patients with the Rosenberg self-esteem scale (RSES), the body cathexis scale (BCS) and the fear of negative appearance evaluation scale (FNAES). Sexarche was also assessed. RESULTS: Amenorrhoea was associated with lower self-esteem (P = 0.03), greater fear of negative appearance evaluation (P = 0.01) and earlier sexarche (P= 0.004). Hyperandrogenism and acne were associated with poorer body satisfaction (P = 0.03, 0.02, respectively). Hirsutism and BMI were negatively associated with all psychological variables (RSES, P = 0.01; BCS, P = 0.05; FNAES, P = 0.02 and RSES, P = 0.03; BCS, P = 0.001; FNAES, P = 0.03, respectively). CONCLUSIONS: Our results suggest that menstrual irregularities might be related to sexarche. Moreover, this study stresses that the treatment of women with PCOS should notably focus on physical but also on psychological and sexual characteristics.

Increasing the revenues from automatic milking by using individual variation in milking characteristics.

The objective of this study was to quantify individual variation in daily milk yield and milking duration in response to the length of the milking interval and to assess the economic potential of using this individual variation to optimize the use of an automated milking system. Random coefficient models were used to describe the individual effects of milking interval on daily milk yield and milking duration. The random coefficient models were fitted on a data set consisting of 4,915 records of normal uninterrupted milkings collected from 311 cows kept in 5 separate herds for 1 wk. The estimated random parameters showed considerable variation between individuals within herds in milk yield and milking duration in response to milking interval. In the actual situation, the herd consisted of 60 cows and the automatic milking system operated at an occupation rate (OR) of 64%. When maximizing daily milk revenues per automated milking system by optimizing individual milking intervals, the average milking interval was reduced from 0.421 d to 0.400 d, the daily milk yield at the herd level was increased from 1,883 to 1,909 kg/d, and milk revenues increased from euro498 to euro507/d. If an OR of 85% could be reached with the same herd size, the optimal milking interval would decrease to 0.238 d, milk yield would increase to 1,997 kg/d, and milk revenues would increase to euro529/d. Consequently, more labor would be required for fetching the cows, and milking duration would increase. Alternatively, an OR of 85% could be achieved by increasing the herd size from 60 to 80 cows without decreasing the milking interval. Milk yield would then increase to 2,535 kg/d and milk revenues would increase to euro673/d. For practical implementation on farms, a dynamic approach is recommended, by which the parameter estimates regarding the effect of interval length on milk yield and the effect of milk yield on milking duration are updated regularly and also the milk production response to concentrate intake is taken into account.

Testing ovarian reserve to predict age at menopause.

In modern society with women delaying pregnancy, predicting the age of the natural menopause with its preceding infertility will allow making informed choices about when to try starting to have children. Also if premature menopause could be predicted in young women, strategies could be instigated to reduce the long term health risks of early estrogen deficiency. This review examines the physiology of ovarian ageing, with the menopause being the final outcome. Long and short term predictive markers of the age of the menopause and the preceding natural infertility are evaluated. Many subtle changes in the endocrine regulation of ovarian function with advancing age may seem interesting but currently are not clinically useful as a predictive test. Examples are changes in concentrations of estradiol, progesterone, luteinizing hormone (LH) and activin, as well as follicle dynamics. Other features hold more promise. Among these are chronological age, family history, anti-Müllerian hormone (AMH), poor response to in vitro fertilization (IVF), basal follicle-stimulating hormone (FSH) and the antral follicle count for long term prediction. For short term prediction, cycle shortening and occurrence of vasomotor symptoms may prove useful. To date, none of these markers has been found to have sufficient predictive accuracy in individual women. Results of new and ongoing longitudinal studies may provide better predictive models. In particular, use of genetic profiles may add to the accuracy of currently known markers.

The endocrine and follicular growth dynamics throughout the menstrual cycle in women with consistently or variably elevated early follicular phase FSH compared with controls.

BACKGROUND: Elevated early follicular phase (EFP) FSH is frequently observed in subfertile patients. In these women, temporary normalization of FSH concentrations is known to occur. We studied the complete endocrine cycle profile of subfertile young women with elevated basal FSH compared with controls. METHODS Daily bloodsampling and ultrasound monitoring in the follicular phase was performed in 22 patients with elevated basal FSH levels (identified in screening) and in 16 controls during one menstrual cycle and for 5 days of the next cycle. RESULTS: Eleven patients showed elevated basal FSH levels in the study cycle ('High, High'; H,H group) whereas 11 had normalized basal FSH levels ('High, Low'; H,L group). Anti-Müllerian hormone (AMH) was lower in both groups. In the H,H group, FSH was higher in all phases of the cycle and both inhibin A and B were lower during the EFP. In the H,L group, FSH was also higher than in controls in the EFP and the late luteal phase and inhibin A was higher in the periovulatory phase. 'Normalization' of Day 3 FSH in women with previously elevated FSH was associated with normalization of inhibin B levels in the preceding luteal phase. CONCLUSIONS: The endocrine cycle profile in younger subfertile patients with consistently elevated basal FSH resembles that in published data from older women and also reflects a low ovarian reserve. Normalization of FSH in association with normal inhibin B suggests a temporary increase of the available cohort.

1-Benzyl-3,3-dichloro-1H-indol-2(3H)-one.

The title compound, C(15)H(11)Cl(2)NO, was synthesized from N-benzyl isatin. The compound crystallizes as stacks of molecules running down the c axis. Molecules within each of these stacks interact with each other through pi-pi and C-H...pi interactions, and interact with neighbouring stacks through C-H...O interactions.

The distribution of FSH receptor isoforms is related to basal FSH levels in subfertile women with normal menstrual cycles.

BACKGROUND: Recently a polymorphic variant of the FSH receptor in which amino acid asparagine (Asn) at position 680 is replaced by serine (Ser) was found. This is associated with higher FSH levels in the early follicular phase and an increased FSH requirement to obtain follicular response in IVF patients. The aim of our study was to test the hypothesis that this receptor isoform occurs more often in regularly menstruating subfertility patients with elevated basal FSH than in those with normal early follicular phase FSH. METHODS: A retrospective cohort study of 38 subfertility patients with a regular menstrual cycle and elevated FSH (>10 IU/l) compared to 40 patients with normal early follicular phase FSH was carried out. DNA was analysed to determine the FSH receptor genotype. RESULTS: The N680S variant on one or both alleles of the FSH receptor gene was significantly more prevalent in patients with elevated FSH (P < 0.05). The homozygous Asn/Asn variant at codon 680 was found in 45% of women with normal FSH and in 21% of women with elevated FSH. The homozygous Ser/Ser receptor variant was present in 12.5% of women with normal FSH and in 21% of patients with elevated FSH. Also the heterozygous combination of both variants Asn/Ser occurred more often in women with elevated FSH (58 versus 42.5%). CONCLUSIONS: The N680S sequence variation of the FSH receptor is found in >75% of the cases with elevated basal FSH and suggests a higher FSH threshold.

Assessment of ovarian reserve. Ovarian biopsy is not a valid method for the prediction of ovarian reserve.

The evaluation of ovarian reserve, often critical for the elderly infertile woman, is notoriously difficult and inaccurate. The place of ovarian biopsy in this evaluation has been hotly disputed for three decades, but not resolved. To examine the feasibility of ovarian biopsy for this purpose, a project was designed to estimate the total number of oocytes in a human ovary and investigate whether any biopsy regimen is representative of the follicular reserve in an individual. Ovaries removed from patients of reproductive age during operations not involving ovarian pathology were utilized to count the number and type of follicles found in multiple biopsies of 2 and 5 mm and in the whole ovary. Representative results taking into account the total number of follicles found in the whole ovary showed that predicted values based on the biopsies were extremely varied. We concluded that due to the huge variation in the distribution of follicles across the surface of the ovary, there is no place for this procedure in clinical evaluation of reproductive ageing in the individual patient.

Post-mortem analysis of samples from a human victim of a fatal poisoning caused by the xanthid crab, Zosimus aeneus.

After ingestion of a specimen of the crab Zosimus aeneus (Xanthidae), an East Timorese adult male died within several hours. Xanthid crabs are known to harbour paralytic shellfish toxins (PSTs), tetrodotoxin and palytoxin. A post-mortem examination did not find any obvious pathological abnormalities. This absence of pathologies is more often associated with PSTs and tetrodotoxin intoxication. A second, yet uneaten specimen of Z. aeneus from the same meal, contained a significant amount of PSTs and these same toxins were identified in the gut contents, blood, liver and urine of the victim. Metabolism of the PSTs occurred with the ingested crab harbouring gonyautoxin 2, gonyautoxin 3 and saxitoxin (STX) whereas neoSTX, decarbamoylSTX and STX dominated the PSTs in the victim's urine. The PST composition in the gut contents, in both their identity and proportion, was intermediate between the eaten crab and the urine suggesting that toxin conversion commenced in the victim's gut. The dose consumed by the victim was calculated to be between 1 and 2 microg STX equivalents/kg based upon the concentration in the remains of the cooked crab. The victim's meal did not consist solely of the toxic crab eaten and the possibility of other food items acting in a synergistic manner with the consumed PSTs cannot be discounted.

Shared bathing and drowning in infants and young children.

OBJECTIVE: A study was undertaken to look at possible risks of shared bathing in early childhood. METHODS: Autopsy databases were searched at the Women's and Children's Hospital and State Coroner's Office, Adelaide, Australia, from January 1963 to December 1999, the Victorian Institute of Forensic Medicine, Melbourne, Australia, from January 1991 to December 1999, and the Children's Hospital-San Diego, San Diego, USA, from January 1990 to December 1999, for all cases registered as drowning in children aged 2 years and under who were in a bath with another child around the time of death. RESULTS: A total of 17 cases were found. The age range of the victims was 8-22 months (average=11.8 months), with a male to female ratio of 10:7. The surviving children (who were all siblings) were significantly older, with an age range of 19-48 months (average=30.4 months), and a male to female ratio of 12:5. (The survivors were on average 18.5 months older than the victims, range=11-32 months). In every case the children had been left unsupervised for variable periods of time. CONCLUSIONS: These cases represented a significant component -- between 22 and 58% -- of bath drownings in the 2 years and under age group. It would appear that shared bathing for young children and infants may only acceptable if adult supervision is constant, and that a young sibling is not an appropriate person to look after an infant or toddler in the bath. While the risk of leaving an infant in a filled bath may be exacerbated if an older child is also present, further population-based studies are required to examine this hypothesis.