Platelet aggregation inhibitors, vitamin K antagonists and risk of subarachnoid hemorrhage.

BACKGROUND: Use of platelet aggregation inhibitors and vitamin K antagonists has been associated with an increased risk of intracranial hemorrhage (ICH). Whether the use of these antithrombotic drugs is associated with an increased risk of subarachnoid hemorrhage (SAH) remains unclear, especially as confounding by indication might play a role. OBJECTIVE: The aim of the present study was to investigate whether use of platelet aggregation inhibitors or vitamin K antagonists increase the risk of SAH. METHODS: We applied population-based case-control, case-crossover and case-time-control designs to estimate the risk of SAH while addressing issues both of confounding by indication and time varying exposure within the PHARMO Record Linkage System database. This system includes drug dispensing records from community pharmacies and hospital discharge records of more than 3 million community-dwelling inhabitants in the Netherlands. Patients were considered a case if they were hospitalized for a first SAH (ICD-9-CM code 430) in the period between 1st January 1998 and 31st December 2006. Controls were selected from the source population, matched on age, gender and date of hospitalization. Conditional logistic regression was used to estimate multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of SAH during use of platelet aggregation inhibitors or vitamin K antagonists. In the case-crossover and case-time-control designs we selected 11 control periods preceding the index date in successive steps of 1 month in the past. RESULTS: In all, 1004 cases of SAH were identified. In the case-control analysis the adjusted OR for the risk of SAH in current use of platelet aggregation inhibitors was 1.32 (95% CI: 1.02-1.70) and in current use of vitamin K antagonists 1.29 (95% CI: 0.89-1.87) compared with no use. In the case-crossover analysis the ORs for the risk of SAH in current use of platelet aggregation inhibitors and vitamin K antagonists were 1.04 (95% CI: 0.56-1.94) and 2.46 (95% CI: 1.04-5.82), respectively. In the case-time-control analysis the OR for platelet aggregation inhibitors was 0.50 (95% CI: 0.26-0.98) and for vitamin K antagonists 1.98 (95% CI: 0.82-4.76). CONCLUSION: The use of platelet aggregation inhibitors was not associated with an increased SAH risk; the modest increase observed in the case-control analysis could be as a result of confounding. The use of vitamin K antagonists seemed to be associated with an increased risk of SAH. The increase was most pronounced in the case-crossover analysis and therefore cannot be explained by unmeasured confounding.

In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up.

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patients with primary unilateral breast cancer were not treated with adjuvant systemic therapy and eligible for the study. In multivariate survival analyses the MAI and M/V-index showed similar hazard ratios (HRs) compared to HRs of histological grade for overall survival (OS) (HR: 1.45, 1.48, and grade II versus grade I (GII/GI) 1.34, grade III versus grade I (GIII/GI) 1.53, respectively) and for breast cancer specific survival (BCSS) (HR: 1.27, 1.57, and (GII/GI) 1.57 (GIII/GI) 2.32, respectively). Other independent prognostic variables for OS and BCSS were age at diagnosis, tumour size, and number of positive lymph nodes. In the present study with long term follow-up, we compared the prognostic value of mitotic activity with that of histological grade and found no advantage for the mitotic activity in predicting either BCSS or OS and concluded that histological grade and the mitotic activity were equally informative in predicting patient outcome. As histological grade is a well established and widely used prognosticator we do not have arguments to replace the histological grade by the mitotic indices MAI or M/V-index.

Influence of panel composition on aesthetic evaluation of adolescent faces.

The objective of this study was to evaluate the influence of professional background, age, gender, and geographical region of panel members on their evaluation of the facial aesthetics of adolescents, and to assess the optimal panel size for epidemiological studies on facial aesthetics. A panel of 76 adult laymen from two different regions (Belgium and The Netherlands) and a panel of 89 orthodontists from the same two regions, evaluated photographic sets (one frontal, one three-quarter smiling, and one lateral view) of 64 adolescents (32 boys, 32 girls) on a visual analogue scale (VAS) in relation to a reference set of photographs. The effects of the characteristics of the panel members on the VAS scores for boys and girls separately, as well as their interactions, were evaluated by multilevel models. The adolescents entered the model as a random effect and four characteristics of the panel members were included in the model as fixed effects. The multilevel model with main effects and first-order interactions revealed that laymen rated adolescents as more attractive than orthodontists. This finding was significant for all laymen, except for older males, and Belgian laymen, when rating girls. Older panel members rated boys significantly more attractive than younger panel members. Males rated adolescents more attractive than females. The latter was significant for all male subgroups, except for the lay male subgroup. There were regional differences. Based on the intraclass correlation coefficient, a panel of seven randomly selected laymen and/or orthodontists is sufficient to obtain reliable results in the aesthetic evaluation of adolescent faces, using photographs and a VAS.

A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility.

BACKGROUND: Controlled ovarian hyperstimulation with intrauterine insemination (IUI) is a widely accepted treatment for unexplained and male subfertility. No consensus exists about the drug of first choice to be used as hyperstimulation. This randomized multicentre trial using a parallel design compares the efficacy of clomiphene citrate (CC) with that of recombinant FSH (rFSH). METHODS: Couples with primary unexplained or male subfertility were randomized to receive CC or rFSH for ovarian hyperstimulation. The treatment was continued for up to four cycles unless pregnancy occurred. Cycles with more than three follicles were cancelled. Cumulative pregnancy rates and live birth rates were primary outcomes. Cancellation during treatment and multiple birth rates are secondary outcomes. Results were analysed following the intention-to-treat principle. RESULTS: Seventy couples with male subfertility and 68 couples with unexplained subfertility were included. Seventy-one women received CC, and 67 received rFSH. Twenty-seven pregnancies were observed in the CC group (38%) and 23 in the rFSH group (34.3%) relative risk (RR) 1.11 [95% confidence interval (95% CI) 0.71-1.73]. The live birth rate was 28.2% (20/71) and 26.9% (18/67) for CC and rFSH, respectively, RR 1.05 (95% CI 0.61-1.80). Overall, the live birth rates per cycle were 10% for CC-stimulated and 8.7% for rFSH stimulated cycles. The total multiple pregnancy rate was 6.0%. Thirty-five cycles (8.6%) were cancelled because of four or more follicles (CC, n = 17; rFSH, n = 18). CONCLUSIONS: In couples with primary unexplained or male subfertility participating in an IUI program, ovarian hyperstimulation can be achieved by CC or rFSH. No significant difference in live birth rates between CC and rFSH was observed. Being less expensive, CC seems the more cost-effective drug and therefore, can be offered as drug of first choice.

Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines.

Identification of genetic copy number changes in glial tumors is of importance in the context of improved/refined diagnostic, prognostic procedures and therapeutic decision-making. In order to detect recurrent genomic copy number changes that might play a role in glioma pathogenesis and/or progression, we characterized 25 primary glioma cell lines including 15 non glioblastoma (non GBM) (I-III WHO grade) and 10 GBM (IV WHO grade), by array comparative genomic hybridization, using a DNA microarray comprising approx. 3500 BACs covering the entire genome with a 1 Mb resolution and additional 800 BACs covering chromosome 19 at tiling path resolution. Combined evaluation by single clone and whole chromosome analysis plus 'moving average (MA) approach' enabled us to confirm most of the genetic abnormalities previously identified to be associated with glioma progression, including +1q32, +7, -10, -22q, PTEN and p16 loss, and to disclose new small genomic regions, some correlating with grade malignancy. Grade I-III gliomas exclusively showed losses at 3p26 (53%), 4q13-21 (33%) and 7p15-p21 (26%), whereas only GBMs exhibited 4p16.1 losses (40%). Other recurrent imbalances, such as losses at 4p15, 5q22-q23, 6p23-25, 12p13 and gains at 11p11-q13, were shared by different glioma grades. Three intervals with peak of loss could be further refined for chromosome 10 by our MA approach. Data analysis of full-coverage chromosome 19 highlighted two main regions of copy number gain, never described before in gliomas, at 19p13.11 and 19q13.13-13.2. The well-known 19q13.3 loss of heterozygosity area in gliomas was not frequently affected in our cell lines. Genomic hotspot detection facilitated the identification of small intervals resulting in positional candidate genes such as PRDM2 (1p36.21), LRP1B (2q22.3), ADARB2 (10p15.3), BCCIP (10q26.2) and ING1 (13q34) for losses and ECT2 (3q26.3), MDK, DDB2, IG20 (11p11.2) for gains. These data increase our current knowledge about cryptic genetic changes in gliomas and may facilitate the further identification of novel genetic elements, which may provide us with molecular tools for the improved diagnostics and therapeutic decision-making in these tumors.

Stress and outcome success in IVF: the role of self-reports and endocrine variables.

BACKGROUND: The aim of this study was to examine the associations between urinary levels of the stress hormones adrenaline, noradrenaline and cortisol during treatment with self reported stress, in order to investigate the mechanism for the previously observed negative association of anxiety and depression with the outcome of IVF/ICSI. METHODS: In a multicentre prospective cohort study, women entering their first cycle of IVF/ICSI treatment were asked to participate. From each participant nocturnal urine samples were collected; pre-treatment, before oocyte retrieval and before embryo-transfer (ET), to assess hormonal concentrations. Additionally, two questionnaires were administered before the start of the treatment to measure anxiety and depression. RESULTS: 168 women completed the questionnaires and collected at least two urine specimens. A significant positive correlation between urinary adrenaline concentrations at baseline and ET and the scores on depression at baseline were found. In women with successful treatment, lower concentrations of adrenaline at oocyte retrieval and lower concentrations of adrenaline and noradrenaline at ET, compared with unsuccessful women, were found. CONCLUSIONS: The significant positive association of adrenaline concentration with pregnancy and with depression suggested that this adrenal hormone could be one of the links in the complex relationship between psychosocial stress and outcome after IVF/ICSI.

Spina bifida and genetic factors related to myo-inositol, glucose, and zinc.

BACKGROUND: Myo-inositol, glucose and zinc and related genetic factors are suggested to be implicated in the etiology of spina bifida. We investigated the biochemical concentrations of these nutrients and polymorphisms in the myo-inositol transporter SLC5A11, myo-inositol synthase ISYNA1, and zinc transporter SLC39A4 in association with spina bifida risk. METHODS: Seventy-six spina bifida triads only were ascertained. In mothers, fathers, and spina bifida children polymorphisms determined were SLC5A11 (544C > T), ISYNA1 (1029A > G), and SLC39A4 (1069C > T). Serum myo-inositol and glucose, and red blood cell zinc concentrations were determined in mothers and spina bifida children. Transmission disequilibrium tests (TDT) were applied to determine associations between the polymorphisms and spina bifida. Associations between biochemical values and genotypes were studied by one-way analysis of variance (ANOVA). Interactions between alleles, biochemical values, and environmental factors were analyzed by conditional logistic regression. RESULTS: No association between SLC5A11, ISYNA1, and SLC39A4 and spina bifida was shown, chi2SLC5A11=0.016, P=0.90; chi2SYNA1=1.52, P=0.22; chi2SLC39A4=0.016, P=0.90; and degrees of freedom (df)=1. Maternal glucose concentrations were comparable for the SLC5A11 genotypes. Significantly lower myo-inositol concentrations were observed in mothers with SLC5A11 CC-genotype, mean (SD) 14.2 (2.6)micromol/L compared to SLC5A11 TT-genotype, 17.0 (3.4)micromol/L, P <0.05 . No significant associations were observed between ISYNA1 and myo-inositol and glucose, and between SLC39A4 and zinc. A significant interaction was demonstrated between a maternal glucose < 4.5 mmol/L and ISYNA1 1029A > G polymorphism on spina bifida risk. CONCLUSION: The combination of maternal glucose < 4.5 mmol/L and ISYNA1 1029A > G polymorphism protects against spina bifida offspring. Moreover, maternal SLC5A11 544C > T polymorphism contributes to the serum myo-inositol concentration. Larger studies should confirm these findings.

Repeated mammographic screening reduces breast cancer mortality along the continuum of age.

OBJECTIVE: The optimal age boundaries for breast cancer screening are still under debate. A case-referent design was used to describe the effect of mammographic screening on breast cancer mortality along the continuum of age, based on a 20 year follow up period. SETTING: The population based breast cancer screening programme in Nijmegen, The Netherlands, which has biennially invited women over 35 years since 1975. METHODS: Cases, defined as women who died from primary breast cancer between 1987 and 1997, were selected from the group of women who received at least one invitation to the screening programme. For 157 cases, 785 women from the same group were selected as referents. Information on the index screening (the screening examination preceding diagnosis of the case) was collected for both cases and referents. The risk of dying from breast cancer was calculated per 10 year moving age group for women who had attended the index screening versus those who had not. RESULTS: The youngest 10 year age group showing an effect in our study were women aged 45-54 at their index screening. Breast cancer mortality for women in this group who attended the index screening was 32% lower, although not significant, than for women who did not (odds ratio (OR) 0.68, 95% confidence interval (95% CI) 0.33 to 1.41). This reduction in risk was not explained solely by an effect in women over 50 because the OR in women aged 45-49 was 0.56 (95% CI 0.20 to 1.61). Reductions in mortality became smaller with increasing age. Nevertheless, for women over 60 at index screening, participation in screening over a maximum 4 year period before diagnosis of the case yielded protective effects at least up to an age around 80. CONCLUSIONS: Although our results are based on a relatively small number of cases, they suggest that even in a programme with a 2 year screening interval there may be a benefit of starting screening around age 45. Also older women who participate at least once every 4 years still have much to gain from screening.

Generalizability of trial results based on randomized versus nonrandomized allocation of OME infants to ventilation tubes or watchful waiting.

The objective was to study the generalizability of trial results by comparing randomized patients to eligible but nonrandomized patients who received the same management. Implementation of trial results is only justifiable when the results can be generalized to the total domain population. The design was a multicentre randomized controlled trial on the effect of early screening and treatment with ventilation tubes on infants with otitis media with effusion. Randomized (n = 187) and nonrandomized eligible patients (n = 133) were followed up. The study population comprised children who were detected by auditory screening at the age of 9-12 months and who were subsequently diagnosed with persistent bilateral otitis media with effusion for 4-6 months. A significant difference was found in the distribution of some prognostic factors: more randomized children had older siblings, did not attend day care and had mothers with a lower educational level than the nonrandomized children. These factors, however, did not modify the outcome. No differences were found in mean hearing levels between the randomized and nonrandomized children: in both the randomized and nonrandomized children ventilation tubes improved the hearing level, especially after 6 months. However, in the long term (12 months), the hearing levels were equal again. The results of the randomized and nonrandomized patients were comparable. The results of this trial appear to be generalizable to the total domain population. The procedure of following up both randomized and nonrandomized patients is recommended when there is concern about selective participation and reduced generalizability.

The effect of short-term ventilation tubes versus watchful waiting on hearing in young children with persistent otitis media with effusion: a randomized trial.

OBJECTIVE: To study the effect of short-term ventilation tubes in children aged 1 to 2 yr with screening-detected, bilateral otitis media with effusion (OME) persisting for 4 to 6 mo, as compared with watchful waiting. DESIGN: Multi-center randomized controlled trial (N = 187) with two treatment arms: short-term ventilation tubes versus watchful waiting. Young children underwent auditory screening; those with persistent (4 to 6 mo) bilateral OME were recruited. RESULTS: The mean duration of effusion over 1-yr follow-up was 142 days (36%) in the ventilation tube (VT) group versus 277 days (70%) in the watchful waiting (WW) group. After 6 mo of follow-up, the pure-tone average in the VT group was 5.6 dB A better than that in the WW group. After 12 mo, most of the advantage in the VT group had disappeared. After the insertion of ventilation tubes, the children with poorer hearing levels at randomization improved more than the children with better hearing levels. The largest difference in hearing levels was found between the children in the VT group whose ventilation tubes remained in situ and the children in the WW group. In the VT children with recurrence of OME, the hearing levels again increased, but remained slightly lower than those in the infants with persistent OME in the WW group. CONCLUSIONS: Ventilation tubes have a beneficial effect on hearing in the short run (6 mo); this effect, however, largely disappears in the long run (12 mo). This is probably due to partial recurrent OME in the VT group and to partial spontaneous recovery in the WW group.

[Public, decentralized and community health networks in Bolivia]. / Redes públicas, descentralizadas y comunitarias de salud en Bolivia.

Health sector reform in Bolivia is based primarily on the principles of decentralization and equity, and with the objectives of improving quality and of expanding health services coverage in rural and low-income areas of the country. As an experiment in reform, the Bolivian Ministry of Health and Social Welfare, the department of La Paz, and the municipality of El Alto signed an agreement with a nongovernmental organization (NGO), transferring to the NGO the overall management of one of the health services networks in El Alto. The transfer was based on a management contract that had process and outcome indicators for the network. A year after implementation began, the preliminary results suggest that through the agreement the quality of management and services has improved, health services coverage has expanded, and the network's primary care services have been strengthened. Bed occupancy rates are generally very low in secondary hospitals in Bolivia, with that figure being just 43% in the department of La Paz in 1999. However, in the second 6 months of operation of the El Alto network the occupancy rate for the network's hospital reached 84%. Between the first 6 months of 1999 and the same period in 2000, outpatient consultations increased by 55% in the network (83% in the hospital and 18% in the network's primary care centers). Over that same period, institutional deliveries increased by 41% and the percentage of deliveries in the primary care centers grew from 5% of the total to 9%. A recent user survey found that 87% of the people receiving care in the network felt highly satisfied with the service they had received, and 75% of the persons surveyed said they would recommend the service to others. These are not typical data for health services in Bolivia. This pilot effort suggests that a change in the organization and management of a health services network, with a separation of the roles of purchaser and provider, combined with management based on results and with community participation in the process, can improve the quality and efficiency of those health services, stimulate demand for them, and increase user satisfaction.

Diverging breast cancer mortality rates in relation to screening? A comparison of Nijmegen to Arnhem and the Netherlands, 1969-1997.

Age-standardised breast cancer mortality rates have been stable for decades. However, rates have started to decline in several Western countries. In countries where population-based screening programmes for breast cancer were introduced in the late 1980s or early 1990s, the key question now is to what extent screening is responsible for the reported declines in mortality. This study compares breast cancer mortality rates in Nijmegen, where a screening programme for breast cancer was introduced in 1975, to a control city, Arnhem, and to the Netherlands as a whole over a 20-year period. Age-standardised breast cancer mortality rates as well as age-standardised mortality ratios were calculated for successive calendar years from 1969 to 1997. Further, a tailor-made period-cohort-group Poisson regression model was fitted. Figures displaying age-standardised mortality rates and ratios showed inconclusive patterns with regard to the expected impact of screening. Depending on when mortality rates were allowed to deviate between populations, the period-cohort-group analysis indicated a non-significant 6% to 16% reduction in breast cancer mortality after 2 decades in favour of the Nijmegen female population. Possible explanations are discussed as to why the mortality reductions reported by randomised trials might not be observed in a public health screening programme, such as the Nijmegen programme, evaluated by comparisons of geographical trends.

Randomised controlled trial of the effect of ventilation tubes (grommets) on quality of life at age 1-2 years.

AIMS: To study the effect of treatment with ventilation tubes on quality of life in children aged 1-2 years with persistent otitis media with effusion (OME), as compared to watchful waiting. METHODS: Multicentre randomised controlled trial (n = 187) with two treatment arms: ventilation tubes and watchful waiting. Children were detected by auditory screening at the age of 9-12 months, and were subsequently diagnosed as having persistent (4-6 months) bilateral OME. Quality of life (TAIQOL and Erickson scales) was measured at 0, 6, and 12 months follow up. RESULTS: There was improvement in quality of life, but the ventilation tube group did not improve significantly more than the watchful waiting group. Although an attempt has been made to identify possible subgroups that benefit more, we were not able to find such subgroups, which might be a result of lack of power in this study. CONCLUSION: Ventilation tubes do not have a substantial incremental effect on the quality of life of infants aged 1-2 years with uncomplicated persistent bilateral OME.

High tPA-expression in primary melanoma of the limb correlates with good prognosis.

To investigate whether the course of primary melanoma disease correlates with expression of the various components of the proteolytic plasminogen activation (PA) system, immunohistochemical stainings for activators of plasminogen (tissue type (tPA) and urokinase type (uPA)), inhibitors of plasminogen activation (type 1 (PAI-1) and type 2 (PAI-2)) and the receptor for uPA (uPAR) were performed on 214 routinely processed melanoma lesions. All lesions were primary cutaneous melanomas, minimally 1.5 mm thick, and derived from patients with only local disease at the moment of diagnosis (clinically stage II (T(3-4)N(0)M(0)), American Joint Committee on Cancer). Median patient follow-up was 6.1 years. Single variables as immunohistochemical staining results (extent of tumour cell staining, pattern of tumour cell staining and for some components also staining of stromal cells), histopathological and clinical parameters as well as treatment variables were analysed in order to assess their prognostic importance, in terms of time to recurrence, time to distant metastasis and duration of survival. The extent of tPA tumour cell positivity, categorized as 0-5%, 6-50% and 51-100%, appeared to be of importance for these end-points. Lesions with 51-100% tPA-positive tumour cells were found to have the best prognosis, whereas lesions with 6-50% tPA-positive tumour cells had the worst. Moreover, the prognostic significance of Breslow thickness, microscopic ulceration and sex was confirmed in this study. Multivariate analyses, incorporating these relevant factors, showed that the extent of tPA tumour cell positivity was an independent prognostic factor for distant metastasis-free interval (P = 0.012) and for the duration of survival (P = 0.043).

The effect of ventilation tubes on language development in infants with otitis media with effusion: A randomized trial.

OBJECTIVE: To study the effectiveness of ventilation tubes on the language development in infants with persistent otitis media with effusion (OME). All existing studies addressed children 3 years of age or older. Currently, OME is detected and treated with ventilation tubes at a younger age. Because of the critical relationship between age, hearing, and language development, we conducted a study of the effects of ventilation tubes on language development in infants 1 to 2 years old with persistent OME. DESIGN: A multicenter, randomized, controlled trial (embedded in a cohort) with 2 treatment arms: 1) treatment with ventilation tubes (VT group; n = 93); or 2) with a period of watchful waiting (WW group; n = 94). Hearing loss and expressive and comprehensive language were assessed every 6 months, while tympanometry and otoscopy were performed every 3 months. Other factors with potential influence on language development were also included: adenoidectomy, hospital, attending day care, sex, age at randomization, educational level of the mother, upper respiratory infections, and the native country of the parents and older siblings. The trial was designed to allow for the detection of a mean difference in language development of 3 months or more between children allocated to the VT and WW groups. RESULTS: No relevant differences were found in expressive or comprehensive language between the 2 groups after adjustment for educational level of the mother, IQ of the child, and differences at baseline. A principal component analysis showed that in the VT group, the children with frequent complaints improved 1.6 months more in comprehensive language than those with no or some complaints. The children with favorable language stimulation, however, did not improve more than the children with less favorable stimulation. No differences were found for expressive language among the various clusters. The probability to improve >3 months in comprehensive language was.48 (95% confidence interval [CI]:.29-.68) for children with highly educated mothers versus.09 (95% CI:.02-.30) for children whose mothers had a low educational level. In the WW group, these changes were.30 (95% CI:.14-.53) and.14 (95% CI:.04-.35), respectively. The probability to improve >4 months in expressive language was.52 (95% CI:.32-.71) for children with highly educated mothers versus.06 (95% CI:.01-.31) for children whose mothers had a low educational level. In the WW group these changes were.42 (95% CI:.23-.64) and.11 (95% CI:.03-.35), respectively. In addition, there were delays in expressive language in both groups compared with their age expected values. The comprehensive language of the children who were effusion-free during the follow-up (n = 54) improved 1.5 months (95% CI: -.2-3.2) more than that of the children who had persistent effusion during the entire follow-up (n = 28). No differences were found for expressive language development. Disregarding the intervention contrast, improvements in hearing seemed to be related to improvements in language development, especially in verbal comprehension. DISCUSSION: In this study, we used the Reynell, Schlichting, and Lexi tests to study the relation between early persistent OME and language development. These tests are directly related to normal language, widely accepted, and validated. It cannot be ruled out that more specific measures such as auditory perception tests would have produced more differences between groups, but the focus was on general language development. A total of 10 children in the WW group received treatment with ventilation tubes during follow-up. A further 11 children dropped out during the trial. A sensitivity analysis with the 10 children who received ventilation tubes did not change the results, and baseline differences were not found between the 11 children who dropped out and those who completed the trial. CONCLUSIONS: In the total group of infants with persistent OME, ventilation tubes did not h

Seasonal variation in the prevalence of persistent otitis media with effusion in one-year-old infants.

The objective of this population-based cohort study was to evaluate the prevalence of persistent otitis media with effusion (OME) and its seasonal variation in 12-month-old infants. All 30099 infants born in the eastern part of The Netherlands between 1 January 1996 and 1 April 1997 were invited for hearing screening, comprising a protocol of three possible tests. Those who failed all three screening tests were referred to an ENT clinic for examination. Prevalences (i.e. the probability that a child would fail all the screening tests) were calculated by searching for the best logistic model for the first, second and third screening test as well as for the visit to an ENT department. By multiplying the prevalences found by the different models with each other, a prevalence was calculated that accounted for increasing age and the timing of the successive hearing tests. Furthermore, 95% confidence intervals were calculated for this age-season-corrected prevalence. When all the children attended the hearing tests at 9, 10, 11 and 12 months of age and when the number of births was the same in all months, the overall prevalence was 4.8% [95% CI 4.3, 5.2]. The highest prevalence (8.0%) was found in April, and the lowest (1.5%) in October. Rates of bilateral OME during the late winter months were twice as high as those during the late summer.

Using a balancing procedure in multicenter clinical trials. Simulation of patient allocation based on a trial of ventilation tubes for otitis media with effusion in infants.

OBJECTIVE: A basic issue in randomized controlled trials (RCTs) is whether we can safely assume comparability between groups at baseline with respect to all potentially important prognostic factors. In other words, did randomization work sufficiently well? In small trials balanced allocation procedures are employed, whereas in large-scale trials simple randomization will do. The question is: When should balancing be considered? METHODS: We performed a simulation study in which we varied the number of categories in the prognostic factors and the number of patients. RESULTS: Simulation showed that, in all instances, a balancing procedure almost always led to perfect or almost perfect balance, while the imbalance with simple randomization was larger. To study the effect of balanced and random allocation on subgroup analyses in our OME trial, we compared the quotient of the width of the confidence intervals (CI). The widest CI in random allocation over the 13 hospitals was on average 13% wider than in balanced allocation. CONCLUSION: Investigators should always consider balanced allocation, especially in categories with a low number of patients and when subgroup analysis over many categories is requested.

Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations.

Fragile X premutations are considered to be a risk factor for premature ovarian failure (POF), which is usually defined as menopause at age <40 years. Since premutations may be inherited from either the mother or the father, we evaluated the influence of the inheritance pattern on the duration of reproductive life in female carriers. The occurrence of POF and age at menopause in women with a paternally inherited fragile X premutation (PIP) were compared to those in women with a maternally inherited fragile X premutation (MIP). We identified 148 women in whom the parental origin of the premutation could be determined. In 109 of these women we were able to establish whether POF had occurred: 82 women had a PIP, and 27 had a MIP. Twenty-three of the women (28%) with a PIP had POF, versus only 1 (3.7%) with a MIP (two -tailed Fisher's exact test; P=. 007). Kaplan-Meier analysis of all 148 premutations showed that the age at menopause was significantly lower in the women with a PIP than in the woman with a MIP (Breslow test in Kaplan-Meier analysis; P=.003). Our data strongly suggest that, when POF occurs in fragile X premutation carriers, a considerable proportion of the premutations are inherited paternally (parent-of-origin effect). We hypothesize that this may be owing to a paternal genomic imprinting effect.