Clinical and self-reported markers of reproductive function in female survivors of childhood Hodgkin lymphoma.

PURPOSE: To evaluate the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes. METHODS: This study was embedded within the DCOG LATER-VEVO study; a Dutch, multicenter, retrospective cohort study between 2004 and 2014. Serum anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, antral follicle count (AFC), and self-reported (first) pregnancy outcomes were evaluated in female childhood HL survivors and controls. RESULTS: 84 HL survivors and 798 controls were included, aged 29.6 and 32.7 years old at time of assessment. Median age at HL diagnosis was 13.4 years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000 mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (< p10) 10.1 [95% CI 4.9; 20.6]; low AFC (< p10) 4.6 [95% CI 2.1; 9.9]; elevated FSH (> 10 IU/l) 15.3 [95% CI 5.7; 41.1], low Inhibin B (< 20 ng/l) 3.6 [ 95% CI 1.7; 7.7], p < 0.001). Pregnancy outcomes were comparable between survivors and controls (± 80% live birth, ± 20% miscarriage). However, survivors were significantly younger at first pregnancy (27.0 years vs 29.0 years, P = 0.04). Adjusted odds-ratio for time to pregnancy > 12 months was 2.5 [95% CI 1.1; 5.6] in survivors, p = 0.031. Adverse outcomes were specifically present after treatment with procarbazine and higher CED-score. CONCLUSION: HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic.

Health-related quality of life in Dutch adult survivors of childhood cancer: A nation-wide cohort study.

AIM: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL. METHODS: Adult CCS (age >18, diagnosed <18, ≥5 years since diagnosis) from the Dutch LATER registry completed the Medical Outcome Study Short Form 36 (SF-36) to measure HRQOL and provided sociodemographic characteristics. Age-adjusted mean SF-36 scale scores of CCS were compared to the Dutch general population for men and women separately using t-tests, with effect size d. Multivariate logistic regression models were built to identify sociodemographic and cancer-related risk factors for impaired physical and mental HRQOL. RESULTS: Both male and female CCS (N = 2301, mean age = 35.4 years, 49.6% female) reported significantly (p ≤ .005) worse HRQOL than the general population on almost all scales of the SF-36 (-.11 ≤ d ≤ -.56). Largest differences were found on vitality and general health perceptions. Significant risk factors (p ≤ .05) for impaired physical HRQOL were female sex, older age at diagnosis, not having a partner, low educational attainment, disease recurrence and exposure to radiotherapy, specifically to lower extremity radiation. Odds ratios (ORs) ranged from 1.6 to 3.7. Significant risk factors for impaired mental HRQOL were age 26-35 years, male sex, not having a partner and low educational attainment. ORs ranged from 1.3 to 2.0. CONCLUSION: Adult CCS had worse HRQOL than the general population. CCS most at risk were those with low educational attainment and without a partner. Adult CCS could benefit from routine surveillance of their HRQOL. Special attention for CCS' vitality and health perceptions and beliefs is warranted.

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

Pregnancy, time to pregnancy and obstetric outcomes among female childhood cancer survivors: results of the DCOG LATER-VEVO study.

PURPOSE: To evaluate pregnancy rates, time to pregnancy (TTP) and obstetric outcomes in female childhood cancer survivors (CCSs) and to identify specific diagnosis- and treatment-related factors associated with these outcomes. METHODS: The study is part of the DCOG LATER-VEVO study, a nationwide multicenter cohort study evaluating fertility among long-term Dutch female CCSs. Data were collected by questionnaire. The current study included 1095 CCSs and 812 controls, consisting of sisters of CCSs and a random sample of women from the general population. RESULTS: Among the subgroup of women who ever had the desire to become pregnant, the chance of becoming pregnant was significantly lower for CCSs than controls (OR 0.5, 95%CI 0.4-0.8). Moreover, TTP was 1.1 times longer for CCSs compared to controls (p = 0.09) and was significantly longer in survivors of CNS and renal tumours. Overall, no differences were found between CCSs and controls regarding the probability of ever having had a miscarriage, still birth, or induced abortion. However, CCSs had a significantly increased risk of delivering preterm (OR 2.2, 95%CI 1.3-3.7) and delivering via caesarean section (OR 1.8, 95%CI 1.2-2.6). Treatment with lower abdominal/pelvic radiotherapy was strongly associated with several adverse obstetric outcomes. CONCLUSION: CCSs are less likely to have ever been pregnant. Among those who do become pregnant, certain subgroups of CCSs are at increased risk of longer TTP. Moreover, as pregnant CCSs, especially those treated with lower abdominal/pelvic radiotherapy, are more likely to develop various adverse obstetric outcomes, appropriate obstetric care is highly advocated.

Measuring vincristine-induced peripheral neuropathy in children with cancer: validation of the Dutch pediatric-modified Total Neuropathy Score.

PURPOSE: The aims were to evaluate the construct validity and reliability of the Dutch version of the pediatric-modified Total Neuropathy Score (ped-mTNS) for assessing vincristine-induced peripheral neuropathy (VIPN) in Dutch pediatric oncology patients aged 5-18 years. METHODS: Construct validity (primary aim) of the ped-mTNS was determined by testing hypotheses about expected correlation between scores of the ped-mTNS (range: 0-32) and the Common Terminology Criteria for Adverse Events (CTCAE) (range: 0-18) for patients and healthy controls and by comparing patients and controls regarding their total ped-mTNS scores and the proportion of children identified with VIPN. Inter-rater and intra-rater reliability and measurement error (secondary aims) were assessed in a subgroup of study participants. RESULTS: Among the 112 children (56 patients and 56 age- and gender-matched healthy controls) evaluated, correlation between CTCAE and ped-mTNS scores was as expected (moderate (r = 0.60)). Moreover, as expected, patients had significantly higher ped-mTNS scores and more frequent symptoms of VIPN compared with controls (both p < .001). Reliability as measured within the intra-rater group (n = 10) (intra-class correlation coefficient (ICCagreement) = 0.64, standard error of measurement (SEMagreement) = 2.92, and smallest detectable change (SDCagreement) = 8.1) and within the inter-rater subgroup (n = 10) (ICCagreement = 0.63, SEMagreement = 3.7, and SDCagreement = 10.26) indicates insufficient reliability. CONCLUSION: The Dutch version of the ped-mTNS appears to have good construct validity for assessing VIPN in a Dutch pediatric oncology population, whereas reliability appears to be insufficient and measurement error high. To improve standardization of VIPN assessment in children, future research aimed at evaluating and further optimizing the psychometric characteristics of the ped-mTNS is needed.

Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome.

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives? SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism. WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences. STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant. PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data. MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse. LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve.

STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.

Reproductive intentions and use of reproductive health care among female survivors of childhood cancer.

STUDY QUESTION: Do female childhood cancer survivors (CCSs) express a decreased desire to have children and do they use reproductive health care more often compared to women without a history of cancer? SUMMARY ANSWER: Overall, no difference was found in the desire to have children between CCSs and controls, whereas CCSs consult a fertility specialist more often, at a younger age, and sooner after their first attempt at conceiving. WHAT IS KNOWN ALREADY: Female CCSs may face a shorter than anticipated reproductive window as a result of their cancer treatment. Little is known about their desire to have children and use of reproductive health care, especially in relation to their former cancer treatment. STUDY DESIGN, SIZE, DURATION: This study is part of the DCOG LATER-VEVO study, a nationwide retrospective cohort study on female fertility in Dutch CCSs. In total, 1749 CCSs and 1673 controls were invited for the study. Data collection took place between January 2008 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on the desire to have children and use of reproductive health care were collected by questionnaire. The control group consisted of sisters from CCSs and females from the general population. In total, 1106 (63%) CCSs and 818 (49%) controls completed the questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no difference was found in the desire to have children between CCSs and controls (86% and 89%, respectively). However, survivors of a CNS tumour were less likely to desire children and CCSs without biological children at time of study were more likely to report that their desire to have children was unfulfilled because of medical reasons (9%), compared to controls (1%). In total, 12% of CCSs ever consulted a fertility specialist compared to 10% of controls (OR = 1.7, 95% CI: 1.3-2.4). Mean (SD) age at time of their first visit was 27.7 (4.4) years for CCSs and 29.9 (3.9) years for controls (P < 0.01). In total, 43% of CCSs consulted a fertility specialist within 12 months after they had started trying to achieve a pregnancy, compared to 27% of controls. Risk factors for consulting a fertility specialist included a previous diagnosis of renal tumour, leukaemia, lymphoma or a CNS tumour, and treatment with alkylating chemotherapy, gonadotoxic radiotherapy or both. In total, 70% of CCSs reported a female factor as cause of subfertility compared to 34% of controls (OR = 4.5, 95% CI: 2.3-8.7) and in this specific group, CCSs seemed more likely to use fertility treatment (OR = 2.9, 95% CI: 1.0-8.2). LIMITATIONS, REASONS FOR CAUTION: Because of the low number of CCSs who used fertility treatment, we were not able to look at specific diagnoses and treatment types associated with using fertility treatment. Nevertheless, we were able to identify diagnostic- and treatment-related risk factors for consulting a fertility specialist. Details regarding consultations with a fertility specialist and fertility treatment were based on self-report and may therefore be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Decisions about parenthood affect all CCSs. It's important to evaluate reproductive intentions and function timely after cancer treatment, so CCSs can be adequately counselled regarding family planning and fertility treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Dutch Cancer Society (Grant no. VU 2006-3622) and the Children Cancer Free Foundation (Project no. 20). TRIAL REGISTRATION NUMBER: NTR2922.

Factors associated with frequency of discussion of or referral for counselling about fertility issues in female cancer patients.

Current practices in counselling of female cancer patients with respect to fertility issues need considerable improvement, particularly given the general underuse of fertility preservation options and the negative impact that infertility can have on quality of life. We investigated the relationship between physicians' and physician-related factors and the frequency of physicians discussing fertility issues and referring to a reproductive specialist. We invited 1,832 physicians in the Netherlands who had treated at least five reproductive-age female cancer patients within the past year to complete a questionnaire. Of the 748 respondents, 406 met our inclusion criteria, and 280 participated. Analysis revealed that 79% of the participants usually or always discuss fertility issues. Specialty, confidence in knowledge regarding fertility issues and a lack of reproductive specialists in their region contributed independently to the variance in the frequency of discussing fertility issues. Moreover, 54% either regularly or always refer. Specialty and frequency of discussion contributed independently to the variance in referral. In conclusion, although high, frequency of discussion of fertility issues is not optimal, and referral seems limited. Patients would benefit from more knowledge among physicians regarding fertility issues and referral options, both in terms of informed choice, and more importantly, quality of life.

Real-World Efficacy of Azelaic Acid 15% Gel for the Reduction of Inflammatory Lesions of Rosacea.

Approximately 16 million Americans have rosacea, an inflammatory cutaneous disorder with central facial erythema, papules, pustules, telangiectasia, flushing, and swelling being among the more commonly recognized features. Overexpression of cathelicidin peptide LL-37 has been implicated in the pathophysiology of rosacea. Azelaic acid has been found to inhibit the pathologic expression of cathelicidin, as well as the hyperactive protease activity that cleaves cathelicidin into LL-37. Given these findings, a small prospective, open-label, interventional trial was undertaken to assess the effects of azelaic acid 15% gel on inflammatory lesions of papulopustular rosacea in a real-world setting. Use of azelaic acid was associated with a significant reduction in inflammatory lesions, which persisted beyond the active treatment phase. Overall, azelaic acid 15% gel is an appropriate initial topical therapy for the treatment of moderate facial rosacea.

Participation rates of childhood cancer survivors to self-administered questionnaires: a systematic review.

This review aimed to assess participation rates of childhood cancer survivors (CCS) invited to fill out a health-related questionnaire. Additionally, effects of study and CCS characteristics on participation rates were examined. PubMed, Web of Science, Ovid (EMBASE) and CINAHL databases were searched. Publications included were questionnaire-based studies among CCS diagnosed with cancer before the age of 21, alive at least 5 years past diagnosis and aged 16 years or older at the time of study. Thirty-five studies were included; the median participation rate was 65%. Sixteen studies reported information about CCS actively declining participation (median rate 5%). Five study characteristics seemed to influence participation rates: the use of reminders and incentives, the option to answer a shortened questionnaire, the recruitment of participants through their general practitioner and a pre-notification before sending out the questionnaire. Furthermore, CCS characteristics related to improved participation were female gender, Caucasian ethnicity and a higher educational level. The results of this study will help to improve the (methodological) quality of future questionnaire-based studies among CCS, thereby increasing our knowledge about late effects among this group of survivors.

Validity of self-reported data on pregnancies for childhood cancer survivors: a comparison with data from a nationwide population-based registry.

STUDY QUESTION: To what degree do records registered in the Netherlands Perinatal Registry (PRN) agree with self-report in a study questionnaire on pregnancy outcomes in childhood cancer survivors (CCSs)? SUMMARY ANSWER: This study suggests that self-reported pregnancy outcomes of CCSs agree well with registry data and that outcomes reported by CCSs agree better with registry data than do those of controls. WHAT IS KNOWN ALREADY: Many studies have shown that childhood cancer treatment may affect fertility outcomes in female CCSs; however, these conclusions were often based on questionnaire data, and it remains unclear whether self-report agrees well with more objective sources of information. STUDY DESIGN, SIZE, DURATION: In an nationwide cohort study on fertility (inclusion period January 2008 and April 2011, trial number: NTR2922), 1420 CCSs and 354 sibling controls were invited to complete a questionnaire regarding socio-demographic characteristics and reproductive history. In total, 879 CCSs (62%) and 287 controls (81%) returned the questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: The current validation study compared the agreement between pregnancy outcomes as registered in the PRN and self-reported outcomes in the study questionnaire. A total of 589 pregnancies were reported in CCSs, and 300 pregnancies in sibling controls, of which 524 could be linked to the PRN. MAIN RESULTS AND THE ROLE OF CHANCE: A high intra-class correlation coefficient (ICC) was found for birthweight (BW) (0.94 and 0.87 for CCSs and controls, respectively). The self-reported BWs tended to be higher than reported in the PRN. For gestational age (GA), the ICC was high for CCSs (0.88), but moderate for controls (0.49). CCSs overestimated GA more often than controls. The Kappa values for method of conception and for method of delivery were moderate to good. Multilevel analyses on the mean difference with regard to BW and GA showed no differences associated with time since pregnancy or educational level. LIMITATIONS, REASONS FOR CAUTION: Not all pregnancies reported could be linked to the registry data. In addition, the completeness of the PRN could not be assessed precisely, because there is no information on the number of missing records. Finally, for some outcomes there were high proportions of missing values in the PRN registry. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that questionnaires are a reliable method of data collection, and that for most variables, self-report agrees well with registry data. STUDY FUNDING/COMPETING INTEREST: This work was supported by the Dutch Cancer Society (grant no. VU 2006-3622) and by Foundation Children Cancer Free. None of the authors report a conflict of interest. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922.

Structure and stability of the negative hydrogen molecular ion.

We present the results of a Coulomb explosion experiment that allows for the imaging of the rovibrational wave function of the metastable H2- ion. Our measurements confirm the predicted large internuclear separation of 6 a.u., and they show that the ion decays by autodetachment rather than by spontaneous dissociation. Imaging of the resulting H2 products reveals a large angular momentum of J = 25 ± 2, quantifying the rotation that leads to the metastability of this most fundamental molecular anion.

Hot water molecules from dissociative recombination of D3O+ with cold electrons.

Individual product channels in the dissociative recombination of deuterated hydronium ions and cold electrons are studied in an ion storage ring by velocity imaging using spatial and mass-sensitive detection of the neutral reaction fragments. Initial and final molecular excitation are analyzed, finding the outgoing water molecules to carry internal excitation of more than 3 eV in 90% of the recombination events. Initial rotation is found to be substantial and in three-body breakup strongly asymmetric energy repartition among the deuterium products is enhanced for hot parent ions.

Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases.

OBJECTIVE: The aim of this study was to evaluate whether values of FSH, LH, estradiol, anti-Müllerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume (OV) determined on day 7 of the hormone-free interval are similar to values measured on days 2-5 of two subsequent natural menstrual cycles. In addition, values measured on day 7 of the hormone-free interval were examined for the purpose of predicting values measured on days 2-5 during the second natural cycle. METHODS: In this study, 25 women using hormonal contraception provided a blood sample and underwent transvaginal ultrasound measurements on day 7 of the hormone-free interval and on cycle days 2-5 of two subsequent natural cycles. Changes were compared by repeated measures ANOVA and multivariate linear regression was used for prediction purposes. RESULTS: Mean (SD) age of the participants was 26.3 (6.2) years. Overall significant decreases in FSH and inhibin B and significant increases in AMH, AFC and ovarian volume values were measured after discontinuation of hormonal contraception (P < 0.001, P = 0.04, P = 0.01, P < 0.001 and P = 0.004, respectively). Significant changes occurred both from day 7 of the hormone-free interval to natural cycle 1 as well as from natural cycle 1 to natural cycle 2. FSH, AMH and AFC values measured during days 2-5 of natural cycle 2 could be predicted by the corresponding values measured on day 7 of the hormone-free interval. CONCLUSION: Hormonal and ultrasound markers of ovarian function in hormonal contraception users measured at the end of the hormone-free interval do not seem to represent subsequent natural early follicular phase values. However, these values can, in some cases (FSH, AMH and AFC), be used to predict early follicular phase values using calculated prediction equations, which need to be validated in future research.

Ultraviolet and visible light photodissociation of H3+ in an ion storage ring.

Ultraviolet and visible photodissociation of a vibrationally excited H(3)(+) ion beam, as produced by standard ion sources, was successfully implemented in an ion storage ring with the aim of investigating the decay of the excited molecular levels. A collinear beams configuration was used to measure the photodissociation of H(3)(+) into H(2)(+) + H fragments by transitions into the first excited singlet state with 266 and 532 nm laser beams. A clear signal could be observed up to 5 ms of storage, indicating that enough highly excited rovibrational states survive on the millisecond time scale of the experiment. The decay into H(2)(+) + H shows an effective time constant between about 1 and 1.5 ms. The initial photodissociating states are estimated to lie roughly 1 eV below the dissociation limit of 4.4 eV. The expected low population of these levels gives rise to an effective cross section of several 10(-20) cm(2) for ultraviolet and some 10(-21) cm(2) for visible light. For using multistep resonant dissociation schemes to monitor rotational populations of cold H(3)(+) in low-density environments, these measurements open promising perspectives.

Anisotropy and molecular rotation in resonant low-energy dissociative recombination.

Angular fragment distributions from the dissociative recombination (DR) of HD(+) were measured with well directed monochromatic low-energy electrons over a dense grid of collision energies from 7 to 35 meV, where pronounced rovibrational Feshbach resonances occur. Significant higher-order anisotropies are found in the distributions, whose size varies along energy in a partial correlation with the relative DR rate from fast-rotating molecules. This may indicate a breakdown of the nonrotation assumption so far applied to predict angular DR fragment distributions.

Implementation of a physical activity intervention for people with rheumatoid arthritis: a case study.

OBJECTIVES: To investigate the potential facilitators and barriers regarding the implementation on a larger scale of an internet-based physical activity intervention which had previously proved to be effective in a randomized, controlled trial concerning sedentary patients with rheumatoid arthritis (RA). METHODS: Assuming a central delivery of the intervention by two trained physical therapists in four regions in the Netherlands, the following activities were employed: the recruitment of potential participants (RA patients), the acquisition of cooperation from referring rheumatologists and the acquisition of reimbursement from regional health insurance companies. Evaluation was done by means of the Reach, Evaluation, Adoption, Implementation and Maintenance framework, of which the following three dimensions were considered relevant: Reach (the number of potential participants), Adoption (readiness for adopting the programme in real life among rheumatologists) and Implementation (the extent to which the intervention could be delivered as intended). Evaluation measures comprised a postal survey among 927 patients with RA in two regions, a telephone survey among rheumatology centres in four regions and consultations with five regional health insurance companies. RESULTS: Seventy-six out of 461 responding RA patients (20%) met the original study inclusion criteria (being sedentary and having access to the internet) and were interested in participation. However, the potential costs of the purchase of a bicycle ergometer and the interference with patients' current physical therapy were obstacles for eligible patients actually to participate. Rheumatologists in four out of five rheumatology centres were willing to participate. All five health insurance companies were willing to reimburse the guidance and feedback by the physical therapist, and the costs of the internet site (estimated costs 271 euro [203 pound] per patient per year), but not the bicycle ergometer (estimated costs 350 euro [262 pound]), provided that current physical therapy would be discontinued. CONCLUSIONS: Facilitators for the implementation of an internet-based physical activity intervention were: (i) a considerable proportion of RA patients were eligible and interested in the programme; (ii) the majority of rheumatologists were willing to refer patients; and (iii) health insurance companies were willing partially to reimburse the intervention. Barriers were the additional costs for patients and their unwillingness to discontinue current physical therapy. These findings underscore the need for additional research into barriers to participation in physical activity interventions among patients with RA, and in reimbursement strategies in particular.