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Quality-adjusted life years are used in cost-effectiveness analyses (CEAs). To calculate QALYs, a "utility" (0-1) is used for each health state induced or prevented by the intervention. We aimed to estimate the impact of quality of life (QoL) assumptions (utilities and durations of health states) on CEAs of cervical cancer screening. To do so, 12 alternative sets of utility assumptions were retrieved from published cervical cancer screening CEAs. Two additional sets were based on empirical QoL data that were integrally obtained through two different measures (SF-6D and EQ-5D) from eight groups of women (total n = 3,087), from invitation for screening to diagnosis with cervical cancer. Per utility set we calculated the number of quality-adjusted days lost (QADL) for each relevant health state in cervical cancer screening, by multiplying the study-specific assumed disutilities (i.e., 1-utility) with study-specific durations of the loss in QoL, resulting in 14 "QADL-sets." With microsimulation model MISCAN we calculated cost-effectiveness of 342 alternative screening programs (varying in primary screening test [Human Papillomavirus (HPV) vs. cytology], starting ages, and screening interval) for each of the 14 QADL-sets. Utilities used in CEAs appeared to differ largely. We found that ten QADL-sets from the literature resulted in HPV and two in cytology as preferred primary test. The SF-6D empirical QADL-set resulted in cytology and the EQ-5D one in HPV as preferred primary test. In conclusion, assumed utilities and health state durations determine cost-effectiveness of cervical cancer screening. Also, the measure used to empirically assess utilities can be crucial for CEA conclusions.

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples 120%). All predictors of the Hunault model were selected into the revised model plus an additional seven Ivvoman's body mass index, cycle length, basal FSH levels, tubal status, history of previous pregnancies in the current relationship [ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 195% CI 0.69 to 0.731 compared with 0.59 195% CI 0.57 to 0.61). (C) 2017 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd

Reliable methods of contraception were introduced in the1960s and enabled women to postpone childbearing and to prevent the birth of not-yet-wanted children. This allowed women to delay the start of their family. However, with increasing female age (>30 years and especially >35 years), there is increased risk of aneuploidy and either miscarriage or a deformed baby. The availability of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) methods allows embryo selection prior to implantation in these women and birth of healthy babies. This allows older women to delay their first pregnancy and plan to have more than 1 child. As a result, the mean age of women at first childbirth increased by 4 to 5 years since the 1970s in most European countries, and the proportion who have their first child at older than 30 years has increased from about 8% to 40%. Both the treatment-independent and treatment-dependent (IVF/ICSI) chances of pregnancy decline with female age. Research on the age-dependent effects has focused on the chance of a first pregnancy and not on having more than 1 child. This study was designed to estimate at what age couples can wait to start a family without compromising their chances of realizing the desired number of children (a 1-, 2-, or 3-child family). The investigators used an established computer simulation model of fertility to simulate a cohort of 10,000 couples in order to assess the chances of realizing a 1-, 2-, or 3-child family. The model used treatment-independent pregnancy chances and pregnancy chances after IVF/ICSI updated with recent IVF success rates. Three levels of importance a couple attaches to achieving a desired family size were singled out: (i) The extremely important level is aimed for at least a 90% success chance; (ii) important (but not at all costs) is aimed at a 75% success chance; and (iii) good to have children (parenthood is not essential) is aimed at a 50% success chance. Based on the computer model, couples who wish to have at least a 90% chance to realize a 1-child family, the age for the female partner to start trying to conceive using IVF should be 35 years or younger. For those desiring 2 children using IVF, the latest starting age should be 31 years, and for 3 children, 28 years. Without IVF, couples who desire a 90% chance should start no later than age 32 years for a 1-child family, at 27 years for a 2-child family, and at 23 years for 3 children. If a 75% or lower chance is acceptable for couples attempting to conceive naturally, they can start 4 to 11 years later for a 1-, 2-, or 3-child family (at 37, 34, and 31 years of age, respectively). Use of IVF has the greatest impact on the starting age for the couples wishing a 90% chance of conceiving. For a 50% or 75% chance at older ages of realizing a 2- or 3-child family, there was little improvement for couples using IVF. The data appeared to be robust for plausible changes in model assumptions. The latest female age at which a couple should start trying to become pregnant is strongly dependent on the importance they attach to achieving a desired family size and on whether IVF is an acceptable option if no natural pregnancy occurs. In the absence of large-scale prospective studies (which would provide more conclusive data), this evidence-based simulation study is the next best option. With continuing improvements in IVF technology, the assumptions on success chances with IVF run the risk of becoming outdated. Therefore, simulations should be updated every 5 to 10 years with new evidence. These findings are important for prospective parents in family planning and for preconception counseling. This information is also useful for inclusion in educational courses in human biology and for increasing public awareness on possibilities and limitations of human reproduction.

Ivermectin is an effective drug for the treatment of human onchocerciasis, a disease caused by the parasitic filarial nematode Onchocerca volvulus. When humans are treated, the microfilariae normally found in the skin are rapidly and very nearly completely eliminated. Nonetheless, after a delay, microfilariae gradually reappear in the skin. This study is concerned with the causes of this delay. Hypotheses are tested by comparing the results of model calculations with skin microfilaria counts collected from 114 patients during a trial of five annual treatments in the focus area of Asubende, Ghana. The results obtained strongly suggest that annual treatment with ivermectin causes an irreversible decline in microfilariae production of approximately 30%/treatment. This result has important implications for public health strategies designed to eliminate onchocerciasis as a significant health hazard.

Objective Referral for colposcopy because of abnormal Pap test results is likely to be distressing, but the extent and duration of these effects are unknown. We aimed to fill this gap. Methods We conducted a prospective observational study at two departments of Obstetrics and Gynecology (an academic and a non-academic setting). Women referred for colposcopy completed questionnaires before colposcopy, and at 1, 3, and 6months afterwards. A reference group of 706 screen participants, aged 29–60years old, was included and completed questionnaires once. Main outcome measures were generic health-related quality of life (HRQoL), assessed through the EQ-5D and the SF-12 physical and mental scores (PCS-12 and MCS-12); anxiety as assessed by STAI-6, and screen-specific anxiety as assessed by the psychological consequences questionnaire (PCQ). Results 154 women responded to the questionnaire, of whom 132 were included in the analyses. Histological results were CIN 1 in 17/115 women (15%) and CIN 2+ in 62 (54%). In 36 women (31%) there was no histologically confirmed neoplasia. Before colposcopy physical HRQoL scores were similar or slightly better than in the reference group, while mental HRQoL (MSC-12) and (screen-specific) anxiety were worse (p Conclusions Referral for gynecological evaluation because of abnormal PAP-test results was distressing. Anxiety – and not the physical burden of management – seemed to be the most bothersome to women. For all CIN-grades, distress disappeared over six months following colposcopy, suggesting a reassuring effect of gynecological management.

OBJECTIVE: To determine to what extent the higher impact of treatment for sexually transmitted diseases (STD) on HIV incidence in Mwanza, Tanzania than in Rakai and Masaka, Uganda might be explained by baseline differences between the trial populations. DESIGN: A re-analysis of baseline data from the three trial populations comparing demography, sexual risk behaviour and HIV/STD epidemiology. METHODS: Data were compared after age-standardization and adjustments for sample selection where necessary. STD rates were also adjusted for the sensitivities and specificities of the diagnostic techniques used. RESULTS: Demographic patterns were similar across populations, apart from effects of AIDS on fertility and mortality (including widowhood) in Uganda. Higher sexual risk behaviours, including younger age of sexual debut, higher numbers of recent partners and lower frequency of condom use, were apparent in Mwanza compared to Masaka and Rakai. High-titre serological syphilis, gonorrhoea, chlamydia infection and trichomoniasis were all more prevalent in Mwanza, except for chlamydia infection in males. There was little difference between sites in the seroprevalence of Herpes simplex virus type-2. Age patterns in the prevalence of short-duration STD and current risk behaviours were similar across sites but all-titre serological syphilis was more prevalent among older participants in Rakai and Masaka than Mwanza. CONCLUSIONS: Differences between trial populations included higher reported risk behaviour and higher rates of curable STD in Mwanza compared to Rakai and Masaka. These differences probably relate to previous reductions in risk behaviour in Uganda and may explain, at least in part, the contrasting results of these trials.

Objective The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. Design The MISCAN–colon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. Results Within an exemplary screening strategy, biennial FIT from the age of 55–75 years, one-sample FIT provided 76.0–97.0 life-years gained (LYG) per 1000 individuals, at a cost of €259 000–264 000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3–12.4 additional LYG compared with one-sample FIT at an extra cost of €50 000–59 000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. Conclusion If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Objective To call attention to the influence of the number of birth-cohorts used in cost-effectiveness analysis (CEA) models on incremental cost-effectiveness ratios (ICERs) under differential discounting. Methods The consequences of increasing the number of birth-cohorts are demonstrated using a CEA of cervical cancer prevention as an example. The cost-effectiveness of vaccinating 12-year-old girls against the human papillomavirus is estimated with the MISCAN microsimulation screening analysis model for 1, 10, 20, and 30 birth-cohorts. Costs and health effects are discounted with equal rates of 4% and alternatively with differential rates of 4% and 1.5% respectively. The effects of increasing the number of cohorts are shown by comparing the ICERs under equal and differential discounting. Results The ICER decreases as the number of cohorts increases under differential discounting, but not under equal discounting. Conclusions The variation of ICERs with the number of cohorts under differential discounting prompts questions regarding the appropriate specification of CEA models and interpretation of their results. In particular, it raises concerns that arbitrary variation in study specification leads to arbitrary variation in results. Such variations could lead to erroneous policy decisions. These findings are relevant to CEA guidance authorities, CEA practitioners, and decision makers. Our results do not imply a problem with differential discounting per se, yet they highlight the need for practical guidance for its use.

Studies with a follow-up of8 weeks have indicated immune-preserving effects of yogurt probiotic supplementation among HIV patients. To evaluate the impact of 25 weeks use of probiotics, a randomized, double blind, controlled study was undertaken on 65 women who were naïve to anti-retroviral treatment.Ten participants were excluded post-randomization due to non-eligibility. Thirty participants were assigned placebo, of whom 25 completed the study versus 19 of 25 completing the study in the probiotics group (p = 0.5). From baseline to 10 weeks follow-up, the CD4 count declined on average 3 CD4 cells/μl (95% Confidence Interval: -97; 91) with placebo versus an increase of 50 cells/μl (95% CI: -61; 162) with probiotics (p = 0.5). From baseline to 25 weeks, the CD4 count increased with 19 cells/μl (95% CI: -90; 129) in the placebo group versus 46 cells/μl (95% CI: -100; 192) with probiotics (p = 0.8). No differences in immune markers, diarrhea incidence or adverse events were observed.Lactobacillus GR-1 and RC-14 may be safely consumed at 2 x 10(9) CFU/day by moderately immune compromised HIV patients but this did not universally preserve immune-function.Women were randomized to receive oral capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 (2 x 10(9) colony forming units) or placebo twice daily for 25 weeks. The CD4 count and immune markers (IgG, IgE, IFNγ and IL-10) were measured at baseline and during follow-up, the occurrence of diarrhea was reported daily.

BACKGROUND: Individuals with a family history of colorectal cancer (CRC) are at increased risk for CRC. Current screening recommendations for these individuals are based on expert opinion. The authors investigated optimal screening strategies for individuals with various degrees of family history of CRC based on a cost-effectiveness analysis. METHODS: The MISCAN-Colon microsimulation model was used to estimate costs and effects of CRC screening strategies, varying by the age at which screening was started and stopped and by screening interval. The authors defined 4 risk groups, characterized by the number of affected first-degree relatives and their age at CRC diagnosis. For all risk groups, the optimal screening strategy had an incremental cost-effectiveness ratio of approximately $50,000 per life-year gained. RESULTS: The optimal screening strategy for individuals with 1 first-degree relative diagnosed after age 50 years was 6 colonoscopies every 5 years starting at age 50 years, compared with 4 colonoscopies every 7 years starting at age 50 years for average risk individuals. The optimal strategy had 10 colonoscopies every 4 years for individuals with 1 first-degree relative diagnosed before age 50 years, 13 colonoscopies every 3 years for individuals with 2 or more first-degree relatives diagnosed after age 50 years, and 15 colonoscopies every 3 years for individuals with 2 or more first-degree relatives of whom at least 1 was diagnosed before age 50 years. CONCLUSIONS: The optimal screening strategy varies considerably with the number of affected first-degree relatives and their age of diagnosis. Shorter screening intervals than the currently recommended 5 years may be appropriate for the highest risk individuals. Cancer 2011;117:4166-74. (C) 2011 American Cancer Society.

Background. Microsimulation models are important decision support tools for screening. However, their complexity makes them difficult to understand and limits realization of their full potential. Therefore, it is important to develop documentation that clarifies their structure and assumptions. The authors demonstrate this problem and explore a solution for natural history using 3 independently developed colorectal cancer screening models. Methods. The authors first project effectiveness and cost-effectiveness of colonoscopy screening for the 3 models (CRC-SPIN, SimCRC, and MISCAN). Next, they provide a conventional presentation of each model, including information on structure and parameter values. Finally, they report the simulated reduction in clinical cancer incidence following a one-time complete removal of adenomas and preclinical cancers for each model. They call this new measure the maximum clinical incidence reduction (MCLIR). Results. Projected effectiveness varies widely across models. For example, estimated mortality reduction for colonoscopy screening every 10 years from age 50 to 80 years, with surveillance in adenoma patients, ranges from 65% to 92%. Given only conventional information, it is difficult to explain these differences, largely because differences in structure make parameter values incomparable. In contrast, the MCLIR clearly shows the impact of model differences on the key feature of natural history, the dwell time of preclinical disease. Dwell times vary from 8 to 25 years across models and help explain differences in projected screening effectiveness. Conclusions. The authors propose a new measure, the MCLIR, which summarizes the implications for predicted screening effectiveness of differences in natural history assumptions. Including the MCLIR in the standard description of a screening model would improve the transparency of these models.

Background A key conclusion of the Four Cities Study, carried out to explore reasons for heterogeneity in the HIV epidemic between two cities in sub-Saharan Africa with relatively low prevalence (Cotonou and Yaounde) and two with high prevalence (Kisumu and Ndola), was that differences in biological cofactors outweighed differences in sexual risk behaviours. The authors explore an alternative hypothesis, that risk behaviours were historically higher in the high-prevalence cities. They also investigate the effects of different prevalence of male circumcision on the HIV epidemics in the four cities. Methods A transmission model was fitted to data from the Four Cities Study. Default scenarios included biological cofactor effects on HIV transmission. Counter-factual scenarios were simulated without biological cofactors, with and without higher historical sexual behaviours, and with various rates of male circumcision. Results Simulated adult HIV prevalence in 1997 for the default scenarios was 3.1%, 7.8%, 28.9% and 27.1% in Cotonou, Yaounde, Kisumu and Ndola, respectively, in line with data. Without biological cofactors, even implausibly high historical levels of risk behaviour in East Africa could not reproduce the observed heterogeneity in the late 1990s. Increasing the proportion of men circumcised in Ndola from 10% to 100% reduced HIV prevalence in 1997 to 7%. Decreasing the proportion circumcised in Yaounde from 100% to 10% increased HIV prevalence to 26%. Conclusions Differences in male circumcision rates are likely to have played a key role in the heterogeneous spread of HIV across Africa. The effect of circumcision interventions can vary depending on the epidemic setting, with a larger effect in more generalised epidemics.

Three strains were isolated and characterized., To characterize the strains of Anaplasma phagocytophilum in wild and domestic animals in China, we isolated the organism from rodents and sheep in northeastern China. We isolated 3 strains (2 from rodents and 1 from sick sheep) through propagation in BALB/c mice and then cell culture in HL60 cells. The 3 isolates were identified by Wright-Giemsa staining, immunofluorescence, and electronic microscopy and were characterized by sequence analyses of the 16S rRNA gene, partial citrate synthase gene, major surface protein 4 gene, and heat shock protein gene. The multiple sequences of the 3 isolates were identical to each other but different from all known strains from other countries. The public health and veterinary relevance of the isolates deserves further investigation.

The costs of computed tomographic colonography (CTC) are not yet established for screening use. In our study, we estimated the threshold costs for which CTC screening would be a cost-effective alternative to colonoscopy for colorectal cancer (CRC) screening in the general population. We used the MISCAN-colon microsimulation model to estimate the costs and life-years gained of screening persons aged 50-80 years for 4 screening strategies: (i) optical colonoscopy; and CTC with referral to optical colonoscopy of (ii) any suspected polyp; (iii) a suspected polyp >= 6 mm and (iv) a suspected polyp 10 mm. For each of the 4 strategies, screen intervals of 5, 10, 15 and 20 years were considered. Subsequently, for each CTC strategy and interval, the threshold costs of CTC were calculated. We performed a sensitivity analysis to assess the effect of uncertain model parameters on the threshold costs. With equal costs ($662), optical colonoscopy dominated CTC screening. For CTC to gain similar life-years as colonoscopy screening every 10 years, it should be offered every 5 years with referral of polyps >= 6 mm. For this strategy to be as cost-effective as colonoscopy screening, the costs must not exceed $285 or 43% of colonoscopy costs (range in sensitivity analysis: 39-47%). With 25% higher adherence than colonoscopy, CTC threshold costs could be 71% of colonoscopy costs. Our estimate of 43% is considerably lower than previous estimates in literature, because previous studies only compared CTC screening to 10-yearly colonoscopy, where we compared to different intervals of colonoscopy screening. (c) 2008 Wiley-Liss, Inc.

Background: There is increasing discussion whether colorectal cancer (CRC) screening guidelines should be individualized by sex and race. Objectives: To determine individualized colonoscopic screening guidelines by sex and race for the average-risk population and to compare the cost-effectiveness of this approach with that of uniform guidelines for all. Design: We used the MISCAN-Colon microsimulation model to estimate life expectancy and lifetime CRC screening and treatment costs in a U.S. cohort of black and white men and women at average risk for CRC. We compared the base-case strategy of no screening and 3 competing colonoscopy strategies: (1) the currently recommended "uniform 10-yearly colonoscopy from age 50 years," (2) a shorter interval "uniform 8-yearly colonoscopy from age 51 years," and (3) "individualized screening according to sex and race." Results: The base-case strategy of no screening was the least expensive, yet least effective. The uniform 10-yearly colonoscopy strategy was dominated. The uniform 8-yearly colonoscopy and individualized strategies both increased life expectancy by 0.0433 to 0.0435 years per individual, at a cost of $15,565 to $15,837 per life-year gained. In the individualized strategy, blacks began screening 6 years earlier, with a 1-year shorter interval compared with whites. The individualized policies were essentially the same for men and women, because the higher CRC risk in men was offset by their shorter life expectancy. The results were robust for changes in model assumptions. Conclusions: The improvements in costs and effects of individualizing CRC screening on a population level were only marginal. Individualized guidelines, however, could contribute to decreasing disparities between blacks and whites. The acceptability and feasibility of individualized guidelines, therefore, should be explored. (Gastrointest Endosc 2009;70:96-108.)

BACKGROUND: Estimates of the fecal occult blood test (FOBT) (Hemoccult II) sensitivity differed widely between screening trials and led to divergent conclusions on the effects of FOBT screening. We used microsimulation modeling to estimate a preclinical colorectal cancer (CRC) duration and sensitivity for unrehydrated FOBT from the data of 3 randomized controlled trials of Minnesota, Nottingham, and Funen. In addition to 2 usual hypotheses on the sensitivity of FOBT, we tested a novel hypothesis where sensitivity is linked to the stage of clinical diagnosis in the situation without screening. METHODS: We used the MIS-CAN-Colon microsimulation model to estimate sensitivity and duration, accounting for differences between the trials in demography, background incidence, and trial design. We tested 3 hypotheses for FOBT sensitivity: sensitivity is the same for all preclinical CRC stages, sensitivity increases with each stage, and sensitivity is higher for the stage in which the cancer would have been diagnosed in the absence of screening than for earlier stages. Goodness-of-fit was evaluated by comparing expected and observed rates of screen-detected and interval CRC. RESULTS: The hypothesis with a higher sensitivity in the stage of clinical diagnosis gave the best fit. Under this hypothesis, sensitivity of FOBT was 51% in the stage of clinical diagnosis and 19% in earlier stages. The average duration of preclinical CRC was estimated at 6.7 years. CONCLUSIONS: Our analysis corroborated a long duration of preclinical CRC, with FOBT most sensitive in the stage of clinical diagnosis. Cancer 2009;115:2410-9. (C) 2009 American Cancer Society.

Background: We will assess to what extent in vitro fertilization (IVF) is effective in ncreasing the number of births overall and whether earlier application of IVF will increase this number. Methods: We simulate 100 000 women trying for their first and second child. Natural and IVF pregnancy rates and infertility rates are age-dependent and based on published data. The age at which women start trying for their first child is based on the Netherlands 2002 data.Three cycles of IVF are given during a 12-month period after 1 or 3 years of trying to conceive unsuccessfully. Main outcome measures are live born deliveries and children, both naturally conceived or after IVF, as well as numbers of singletons, twins and triplets, the total fertility rate (TFR) and the number of IVF cycles performed. Results: Full access to IVF after 3 years increases the TFR by 0.08 children. Applying IVF after 1 year leads to an additional TFR increase of 0.04, with double the number of IVF cycles and twin and triplet children, and a shift from naturally conceived children to IVF children. Conclusions: Full access to IVF after 3 years is important. It does increase the TFR. Early availability of IVF would further increase the TFR, but with side-effects and high costs. Key words: in vitro fertilization / assisted reproduction / total fertility rate / multiple pregnancies / IVF policy

Decision making on infertility treatment in low-income countries (LIC) assumes answers to quite a few questions: how should the infertility problem be defined? How often does infertility occur? What is the burden-of-disease of infertility? What is the income in LIC, and what can be spend on health care? How cheap should IVF be in order to be accessible to a considerable part of the population? With what alternative health interventions should infertility treatment be compared? How cost-effective should IVF be in order to compete with those other interventions? These questions will be discussed. The emphasis is on the situation in Sub-Saharan Africa (SSA). It is concluded that a place for ART in a health care package is not straightforward. Many of the questions are not or only partially answered. Moreover, cheap and effective ART has yet to be developed and tested. From the limited evidence available for each of the questions, it could be calculated that an IVF cycle should cost between 50 and 75 dollar in order to be a candidate for the inclusion in a health package in SSA. This estimate can easily change considerably when in the future the calculations will be based on thorough research. Thus, a targeted research programme for answering the open questions, especially on quality-of-life implications of infertility in different societies, is the preferred option for facilitating the future evaluation of ART in LIC.

Not the final published version, BACKGROUND: Evidence regarding the effectiveness of sexually transmitted infection (STI) treatment for HIV prevention in Africa is equivocal, leading some policy makers to question whether it should continue to be promoted for HIV control. We explore whether treating curable STIs remains a cost-effective HIV control strategy in Africa. METHODS: The model STDSIM was fitted to the characteristics of 4 populations in East and West Africa. Over the simulated HIV epidemics, the population-attributable fractions (PAFs) of incident HIV attributable to STIs, the impact of syndromic STI management on HIV incidence, and the cost per HIV infection averted were evaluated and compared with an estimate of lifetime HIV treatment costs (US $3500). RESULTS: Throughout the HIV epidemics in all cities, the total PAF for. all STIs remained high, with > or = 50% of HIV transmission attributed to STIs. The PAF for herpes simplex virus type 2 increased during the epidemics, whereas the PAF for curable STIs and the relative impact of syndromic management decreased. The models showed that the absolute impact of syndromic management remains high in generalized epidemics, and it remained cost-saving in 3 of the 4 populations in which the cost per HIV infection averted ranged between US $321 and $1665. CONCLUSION: Curable STI interventions may remain cost-saving in populations with generalized HIV epidemics, particularly in populations with high-risk behaviors or low male circumcision rates.

Background: Obesity is increasing rapidly among women all over the world. Obesity is a known risk factor for subfertility due to anovulation, but it is unknown whether obesity also affects spontaneous pregnancy chances in subfertile, ovulatory women. Methods: We evaluated whether obesity affected the chance of a spontaneous pregnancy in a prospectively assembled cohort of 3029 consecutive subfertile couples. Women had to be ovulatory and had to have at least one patent tube, whereas men had to have a normal semen analysis. Time to spontaneous ongoing pregnancy within 12 months was the primary endpoint. Results: The probability of a spontaneous pregnancy declined linearly with a body mass index (BMI) over 29 kg/m(2). Corrected for possible related factors, women with a high BMI had a 4% lower pregnancy rate per kg/m(2) increase [hazard ratio: 0.96 (95% CI 0.91-0.99)]. Conclusions: These results indicate that obesity is associated with lower pregnancy rates in subfertile ovulatory women.

Not the final published version, BACKGROUND AND OBJECTIVE: Male circumcision (circumcision) reduces HIV incidence in men by 50-60%. The United Nations Joint Programme on HIV/AIDS (UNAIDS) recommends the provision of safe circumcision services in countries with high HIV and low circumcision prevalence, prioritizing 12-30 years old HIV-uninfected men. We explore how the population-level impact of circumcision varies by target age group, coverage, time-to-scale-up, level of risk compensation and circumcision of HIV infected men. DESIGN AND METHODS: An individual-based model was fitted to the characteristics of a typical high-HIV-prevalence population in sub-Saharan Africa and three scenarios of individual-level impact corresponding to the central and the 95% confidence level estimates from the Kenyan circumcision trial. The simulated intervention increased the prevalence of circumcision from 25 to 75% over 5 years in targeted age groups. The impact and cost-effectiveness of the intervention were calculated over 2-50 years. Future costs and effects were discounted and compared with the present value of lifetime HIV treatment costs (US$ 4043). RESULTS: Initially, targeting men older than the United Nations Joint Programme on HIV/AIDS recommended age group may be the most cost-effective strategy, but targeting any adult age group will be cost-saving. Substantial risk compensation could negate impact, particularly if already circumcised men compensate. If circumcision prevalence in HIV uninfected men increases less because HIV-infected men are also circumcised, this will reduce impact in men but would have little effect on population-level impact in women. CONCLUSION: Circumcision is a cost-saving intervention in a wide range of scenarios of HIV and initial circumcision prevalence but the United Nations Joint Programme on HIV/AIDS/WHO recommended target age group should be widened to include older HIV-uninfected men and counselling should be targeted at both newly and already circumcised men to minimize risk compensation. To maximize infections-averted, circumcision must be scaled up rapidly while maintaining quality.

SUMMARYLYMFASIM is a simulation model for lymphatic filariasis transmission and control. We quantified its parameters to simulate Wuchereria bancrofti transmission by Anopheles mosquitoes in African villages, using a wide variety of reported data. The developed model captures the general epidemiological patterns, but also the differences between communities. It was calibrated to represent the relationship between mosquito biting rate and the prevalence of microfilariae (mf) in the human population, the age-pattern in mf prevalence, and the relation between mf prevalence and geometric mean mf intensity. Explorative simulations suggest that the impact of mass treatment depends strongly on the mosquito biting rate and on the assumed coverage, compliance and efficacy. Our sensitivity analysis showed that some biological parameters strongly influence the predicted equilibrium pre-treatment mf prevalence (e.g. the lifespan of adult worms and mf). Other parameters primarily affect the post-treatment trends (e.g. severity of density dependence in the mosquito uptake of infection from the human blood, between-person variability in exposure to mosquito bites). The longitudinal data, which are being collected for evaluation of ongoing elimination programmes, can help to further validate the model. The model can help to assess when ongoing elimination activities in African populations can be stopped and to design surveillance schemes. It can be a valuable tool for decision making in the Global Programme to Eliminate Lymphatic Filariasis.

In 1991 the World Health Assembly decided to 'eliminate leprosy as a public health problem' by the year 2000. Elimination was defined as reducing the global prevalence of the disease to less than 1 case per 10,000. In 2000 the World Health Organization (WHO) announced that elimination was reached globally. Conventionally control of disease is defined as the reduction of disease burden to a locally acceptable level. Elimination of disease is defined as the reduction to zero of the incidence in a defined geographical area, and eradication is defined as the permanent reduction to zero of the worldwide incidence of infection caused by a specific agent. In leprosy however, WHO limited elimination to control instead of transmission, by using prevalence instead of incidence of disease. Leprosy statistics usually report on prevalence and new case detection. Prevalence is linked to length of treatment, which has changed over time. Trends in new case detection rates only reflect trends in incidence rates when no changes occur in case detection, but in the past 25 years case detection in leprosy has been determined strongly by operational factors. For the leprosy elimination strategy it was assumed that MDT would reduce transmission of M. leprae, but there is no convincing evidence for this. Data for evaluating the impact of MDT on transmission are not readily available because leprosy has a long incubation period. Also declines in case detection may have other causes, such as BCG vaccination. Mathematical modelling of the transmission and control of leprosy showed that the elimination strategy reduces transmission slowly, with a predicted annual decline in incidence ranging from 2% to 12%. Early case finding was the key factor to attain this decline. Future projections of the global leprosy burden indicated that 5 million new cases would arise between 2000 and 2020, and that in 2020 there would be 1 million people with WHO grade 2 disability. It is concluded that substantial progress has been made to control leprosy, but when elimination of disease is defined as the reduction to zero of the incidence, leprosy is definitely not eliminated. To attain elimination of leprosy it is necessary to find effective interventions to interrupt transmission of M. leprae and practical diagnostic tools to detect levels of infection that can lead to transmission. This requires extensive research in the areas of epidemiology and microbiology.

It is expected that, as women continue to postpone childbearing, more of them will present to fertility centers with age-related subfertility. The most widely used measure of ovarian reserve is the basal blood level of follicle-stimulating hormone (FSH) in the early follicular phase of the cycle. Its predictive value seems limited in the setting of in vitro fertilization, and its value for screening a general subfertile population is not clear. This prospective cohort study, carried out at 19 fertility centers in the Netherlands, enrolled subfertile ovulatory women lacking 2-sided tubal pathology whose partners had normal sperm parameters. The fertility workup included an estimate of basal FSH on cycle day 3. The study population consisted of 3270 consecutive couples followed up at 12 months, 562 of whom (16%) had a spontaneous ongoing pregnancy. Four of these were multiple pregnancies. Another 61 couples had unsuccessful pregnancies. A basal FSH of 8 IU/L or higher was associated with a reduced likelihood of spontaneous ongoing pregnancy. The hazard ratio was 0.93, with a 95% confidence interval of 0.87-0.98. On multivariable analysis, female age, cycle length, and an FSH level of 8 IU/L or higher were strong negative predictors for spontaneous ongoing pregnancy. In analyzing 3219 couples, adding FSH to a prediction model based on female age, duration of subfertility, previous pregnancy, referral status, and semen analysis altered the likelihood of conceiving spontaneously from 30% or more to less than 30%. Compared with women whose basal FSH was less than 8 IU/L, the probability of conceiving was reduced 40% if the basal FSH was 15 IU/L, and 58% if it was 20 IU/L. A basal FSH level of 8 IU/L or higher was associated with decreased fecundity in ovulatory women in this study, independently of female age and cycle length. This finding does not, however, often lead to altered management, and for this reason the investigators do not recommend routinely estimating basal FSH in subfertile couples.

Objective: To determine if the differences in risk behaviours, the proportions of males circumcised and prevalences of sexually transmitted infections (STIs) observed in two African cities with low prevalence of HIV (Cotonou, Benin, and Yaounde, Cameroon) and two cities with high prevalence (Kisumu, Kenya, and Ndola, Zambia) could explain the contrasting HIV epidemics in the four cities. Methods: An individual-based stochastic model, STDSIM, was fitted to the demographic, behavioural and epidemiological characteristics of the four urban study populations based on data from the Four Cities Study and other relevant sources. Model parameters pertaining to STI and HIV natural history and transmission were held constant across the four populations. The probabilities of HIV, syphilis and chancroid acquisition were assumed to be doubled among uncircumcised males. A priori plausible ranges for model inputs and outputs were defined and sexual behaviour characteristics, including those pertaining to commercial sex workers (CSWs) and their clients, which were allowed to vary across the sites, were identified based on comparisons of the empirical data from the four sites. The proportions of males circumcised in the model, 100% in Cotonou and Yaounde, 25% in Kisumu and 10% in Ndola, were similar to those observed. A sensitivity analysis was conducted to assess how changes in critical parameters may affect the model fit. Results: Population characteristics observed from the study that were replicated in the model included younger ages at sexual debut and marriage in east Africa compared with west Africa and higher numbers of casual partners in the past 12 months in Yaounde than in the other three sites. The patterns in prevalence of STIs in females in the general population and CSWs were well fitted. HIV prevalence by age and sex and time trends in prevalence in the model were consistent with study data with the highest simulated prevalences in Kisumu and Ndola, intermediate in Yaounde and lowest in Cotonou. The sensitivity analysis suggested that the effect of circumcision on the development of the HIV epidemics may have been mediated indirectly by its effect on ulcerative STI. Conclusions: The contrasting HIV epidemics in east and west Africa could be replicated in our model by assuming that male circumcision reduced susceptibility to HIV, syphilis and chancroid. Varying rates of male circumcision may have played an important role in explaining the strikingly different HIV epidemics observed in different parts of sub-Saharan Africa.

Although mass screening for cervical cancer has been operational for more than 2 decades in the Netherlands, 700 women are still diagnosed with this cancer each year (9 per 100,000). We investigated these cases, in order to evaluate opportunities to further increase the effectiveness of the programme. We analyzed the screening history of women diagnosed with cervical cancer between 1994-1997 using the Dutch national pathology file that includes cervical cytology and histological results. More than half of the cases did not have previous preventive cervical smears, and another 30% had never been invited to the programme because of their age. In the future, we estimate that two thirds of all Dutch women with invasive cervical cancer will be unscreened or under-screened, based on current screening participation of more than 70%. We conclude that increasing screening participation has much more potential for further reducing cervical cancer incidence than reducing the screening interval, increasing the age range or having a screening test with higher sensitivity.

The conventional direct referral to colposcopy of persistent borderline or mildly dyskaryotic (BMD) smears in cervical cancer screening leads to considerable unnecessary referrals and associated anxiety and costs. This may be improved by including testing for oncogenic human papillomavirus (HPV) in the triage. We assessed costs and side effects (referrals, treatments and time in follow-up) for 3 possible HPV triage strategies (immediate HPV testing, a 6-month delay in HPV testing, a 2-stage combination of both) and compared them with the conventional strategy. The assessments are based on recent Dutch data from various national databases and trials. We estimated that the referral rate could be reduced by 49, 58 and 58% with immediate, delayed and 2-stage HPV testing, respectively. As a consequence, the average length of follow-up, as well as average costs, also decrease. Therefore, we advocate including HPV testing before referring to colposcopy. Among the 3 HPV strategies, analysis of additional aspects favors implementation of immediate HPV testing.

Objective: To assess the effectiveness of controlled ovarian hyperstimulation (COH) in intrauterine insemination (IUI) for subfertile couples with an abnormal postcoital test and a poor prognosis. Design: Randomized clinical trial. Setting: Twenty-four fertility centers in the Netherlands. Patient(s): Subfertile couples with a well-timed nonprogressive PCT and additional factors that reduce fertility. Intervention(s): Couples were randomly allocated to three cycles of IUI with COH or three cycles of IUI without COH. Main Outcome Measure(s): Ongoing pregnancy within three IUI cycles. Result(s): We randomly allocated 132 couples to IUI with COH, and 133, to IUI without COH. We observed 33 pregnancies (25%) in the couples allocated to IUI with COH, of which 28 were ongoing (21%), vs. 28 pregnancies (21%) in the couples allocated to IUI without COH, of which 23 were ongoing (17%; relative risk of an ongoing pregnancy, 1.2; 95% confidence interval, 0.75 to 2.0). Two multiple pregnancies occurred in the IUI with COH group, and one, in the IUI without COH group. Conclusion(s): In couples with an abnormal PCT and a poor prognosis, IUI with COH leads to pregnancy rates comparable to those for IUI without COH. We propose to perform IUI without COH in couples with an abnormal PCT.

Seven models have estimated the contribution of screening to the decrease in U.S. breast cancer mortality between 1975 and 2000. We will investigate whether the model estimates of the mortality reduction due to screening are associated with intermediate outcome measures (IOMs). Detection rates at screening, 1- and 2-year sensitivity, program sensitivity, and incidence of advanced tumors are used as IOMs. Moreover, the model parameters preclinical duration and sensitivity are analyzed. The correlation of IOMs with mortality is assessed for actual U.S. screening and for an intensive screening scenario, with annual screening at ages 40-79 years with 100% participation. Also, 12 alternative screening scenarios are run for one of the models, and within-model correlation between IOMs and mortality reduction is described. Resulting correlations between IOMs and mortality reduction are mostly weak. For 2-year sensitivity and the incidence of advanced tumors, correlations are high in the intensive screening scenario. Within-model correlations are strong for incidence of advanced tumors and program sensitivity. Intermediate outcome measures have limited potential in predicting the impact of mammographic screening on mortality. Incidence of advanced tumors and program sensitivity are measures that merit further consideration as surrogates for mortality reduction.

The MISCAN-Fadia model was used to analyze the impact of screening and adjuvant treatment on U.S. breast cancer mortality between 1975 and 2000. MISCAN-Fadia uses the concept of "fatal diameter" to model survival and screening benefit and is based on continuous tumor growth. It consists of four major components: population, natural history, screening, and treatment. Population parameters were quantified using U.S. population data. Most natural history and screening parameters were fitted to the Swedish Two County screening trial data; some were based on Surveillance, Epidemiology, and End Results data. Adjuvant treatment parameters were quantified using data from the Early Breast Cancer Trialists' Collaborative Group's meta-analysis. The simulated trend in incidence matches the observed trend reasonably well; the simulated mortality is equal to the observed in 1975 but becomes increasingly too high in 2000. We estimate that screening leads to a 15% and adjuvant treatment to a 21% mortality reduction in the year 2000.

Polymerase chain reaction integrated with sequence analysis was carried out to investigate the natural Anaplasma phagocytophilum infection in ticks and rodents from a forest area of Jilin Province, China. Four (4.0%) of 100 Ixodes persulcatus and 2 (0.7%) of 286 Dermacentor silvarum ticks collected by flagging vegetation were positive. Nine (8.8%) of 102 rodents were infected, as well as 2 (2.8%) of 71 I. persulcatus parasitizing on 25 rodents. The nucleotide sequences of 1442-bp A. phagocytophilum 16S rRNA gene amplified from rodents and ticks were identical to each other and to that previously reported in Heilongjiang Province of China (GenBank accession no. AF205140), but different from those of other countries. The sequences of 357-bp partial citrate synthase gene from the above specimens were homologic, and varied from known A. phagocytophilum agents. These findings add new information on the ecologic features of A. phagocytophilum and indicate the threat of anaplasmosis in the area.

Summary Objectives To determine the efficacies of combinations of ivermectin or diethylcarbamazine and albendazole, which are recommended for use in mass treatment programmes against lymphatic filariasis. Method Review of published trends in microfilarial (mf) intensities after treatment with these combination therapies. By fitting a mathematical model of treatment effects to the trial data, we quantified the efficacy of treatment, distinguishing between the killing of mf (mf loss) and a reduction in mf production by adult worms (worm-productivity loss). After diethylcarbamazine–albendazole treatment mf density dropped immediately, then slowly but steadily decreased further (four trials). After ivermectin–albendazole treatment, mf densities immediately dropped to near-zero levels, followed by a small increase (five trials). For diethylcarbamazine–albendazole treatment the average mf loss was approximately 83% (ranging from 54% to 100% in the different studies) and worm-productivity loss was 100% (in all studies). For ivermectin–albendazole treatment, average mf loss was 100% (ranging from 98% to 100%) and worm productivity loss was 96% (ranging from 83% to 100%). The effects were dose-dependent. Sensitivity analysis showed that the estimates did not depend on assumptions on worm lifespan or premature period and little on assumptions on mf lifespan. Conclusion The two therapies differ with respect to their direct effect on mf, but both are highly effective against adult worms. If mass treatment with these combination therapies achieves high coverage, they can have a large impact on lymphatic filariasis transmission. Objectifs Comparer l'efficacite des combinaisons de l'ivermectin ou la diethylcarbamazine avec l'albendazole dans les programmes de traitement de masse de la filariose lymphatique. Methode Revue des profils des intensites microfilariques apres administration de ces traitements combines. En incorporant un modele mathematique des effets des traitements aux donnees d'essais, nous avons pu quantifier l'efficacite du traitement en distinguant entre mort induite des microfilaires et reduction de la production de microfilaires par les vers adultes (perte de productivite des vers). Suite au traitement a la diethylcarbamazine-albendazole, la densite de microfilaires a chute immediatement, puis a diminue lentement mais constamment (dans 4 essais). Suite au traitement a l'ivermectin-albendazole, la densite de microfilaires a chute immediatement jusqu’a pres de zero, suivi d'une legere augmentation (dans 5 essais). Pour le traitement a la diethylcarbamazine-albendazole la perte moyenne de microfilaires etait approximativement de 83% (allant de 54 a 100% selon les essais) et la perte de productivite des vers etait de 100% dans tous les essais. Pour le traitement a l'ivermectin-albendazole, la perte moyenne de microfilaires etait de 100% (allant de 98 a 100%) et la perte de productivite des vers etait de 96% (allant de 83 a 100%). Les effets des traitements etaient dose dependants. L'analyse des sensibilites des essais a montre que les estimations ne dependaient pas des assomptions sur la duree de vie ou la periode premature des vers et dependaient peu des assomptions sur la duree de vie des microfilaires. Conclusion Les deux formes de traitement different par leur effet direct sur les microfilaires, mais toutes les deux sont tres efficaces sur les vers adultes. L'administration d'un traitement de masse avec ces combinaisons sur une couverture etendue pourrait avoir un impacte important sur la transmission de la filariose. Objetivos Comparar las eficacias de las combinaciones de ivermectina o dietilcarbamazina con albendazol en programas masivos de tratamiento contra la filariasis linfatica. Metodo Revision de lo publicado sobre las tendencias en la intesidad de microfilarias (im) despues del tratamiento con estas terapias de combinacion. Estimando un modelo matematico sobre los efectos del tratamiento a los datos del ensayo, cuantificamos la eficacia del tratamiento, distinguiendo entre la mortalidad de im (perdida de im) y la reduccion en la productividad de la im por parte de las lombrices adultas (perdida de productividad de las lombrices). Despues del tratamiento con dietilcarbamazina- albendazol, la densidad de im cayo inmediatamente, y posteriormente continuo su disminucion de forma constante (4 ensayos). Despues de tratamiento con ivermectina- albendazol, las densidades de im cayeron a un nivel cercano a cero, seguido por un pequeno aumento (5 ensayos). La perdida media de im para el tratamiento con dietilcarbamazina- albendazol fue de aproximadamente el 83% (entre 54–100% en los diferentes estudios) y la perdida de productividad de las lombrices fue del 100% (en todos los estudios). En cuanto al tratamiento con ivermectina- albendazol, la perdida media de im fue del 100% (entre 98–100%) y la perdida de productividad de las lombrices fue del 96% (entre 83–100%). Los efectos fueron dosis dependientes. El analisis de sensibilidad demostro que las estimaciones no dependian de asunciones sobre el periodo de vida de la lombriz o un periodo prematuro y pocas asunciones sobre el periodo de vida de im. Conclusiones Las dos terapias difieren con respecto a su efecto directo sobre el im, pero ambas son altamente efectivas contra las lombrices adultas. Si se alcanzara una alta cobertura de tratamiento con estas terapias combinadas, podrian tener un gran impacto sobre la transmision de la filariasis linfatica.

Sixteen vignettes of subfertile couples were constructed by varying fertility history, post-coital test, sperm motility, FSH concentration and Chlamydia antibody titre (CAT). Thirty-five gynaecologists estimated probabilities of treatment-independent pregnancy, intrauterine insemination (IUI) and IVF. Thereafter, they chose IUI, IVF or no treatment. The relative contribution of each factor to probability estimates and to subsequent treatment decisions was calculated. Duration of subfertility and maternal age were the most important contributors for gynaecologists' estimates of treatment-independent pregnancy [relative contribution (RC) 41, 26%]. Maternal age and FSH concentration were the most important contributors in the estimates for IUI (RC: 51, 25%) and for IVF (RC: 64, 31%). The decision to start IVF was mainly determined by maternal age, duration of subfertility, FSH concentration and CAT. The relative contribution of maternal age and duration of subfertility was in concordance with existing prediction models, whereas previous pregnancy and FSH concentration were under- and overestimated respectively. In conclusion, maternal age, duration of subfertility and FSH concentration are the main factors in clinical decision-making in subfertility. Gynaecologists overestimate the importance of FSH concentration, but underestimate that of a previous pregnancy, as compared with their importance reported in prediction models and guidelines.

The aim of this study was to quantify the potential reduction in sample size that can be achieved by adjustment for predictors of outcome in traumatic brain injury (TBI) trials. We used individual patient data from seven therapeutic phase III randomized clinical trials (RCTs; n = 6166) in moderate or severe TBI, and three TBI surveys (n = 2238). The primary outcome was the dichotomized Glasgow Outcome Scale at 6 months (favorable/unfavorable). Baseline predictors of outcome considered were age, motor score, pupillary reactivity, computed tomography (CT) classification, traumatic subarachnoid hemorrhage, hypoxia, hypotension, glycemia, and hemoglobin. We calculated the potential sample size reduction obtained by adjustment of a hypothetical treatment effect for one to seven predictors with logistic regression models. The distribution of predictors was more heterogeneous in surveys than in trials. Adjustment of the treatment effect for the strongest predictors (age, motor score, and pupillary reactivity) yielded a reduction in sample size of 16-23% in RCTs and 28-35% in surveys. Adjustment for seven predictors yielded a reduction of about 25% in most studies: 20-28% in RCTs and 32-39% in surveys. A major reduction in sample size can be obtained with covariate adjustment in TBI trials. Covariate adjustment for strong predictors should be incorporated in the analysis of future TBI trials.

BACKGROUND. Although colorectal cancer (CRC) is the second leading cause of cancer death in the U.S., available interventions to reduce CRC mortality are disseminated only partially throughout the population. This study assessed the potential reduction in CRC mortality that may be achieved through further dissemination of current interventions for risk-factor modification, screening, and treatment. METHODS. The MISCAN-COLON microsimulation model was used to simulate the 2000 U.S. population with respect to CRC risk-factor prevalence, screening use, and treatment use. The model was used to project age-standardized CRC mortality from 2000 to 2020 for 3 intervention scenarios. RESULTS. Without changes in risk-factor prevalence, screening use, and treatment use after 2000, CRC mortality would decrease by 17% by the Year 2020. If the 1995 to 2000 trends continue, then the projected reduction in mortality would be 36%. However, if trends in the prevalence of risk-factors could be improved above continued trends, if screening use increased to 70% of the target population, and if the use of chemotherapy increased among all age groups, then a 49% reduction would be possible. Screening drove most (23%) of the projected mortality reduction with these optimistic trends; however, decreasing risk-factors (16%) and increasing use of chemotherapy (10%) also contributed substantially. The contribution of risk-factors may have been overestimated, because effect estimates could not be obtained from randomized controlled trials. CONCLUSIONS. Currently available interventions for risk-factor modification, screening, and treatment have the potential to reduce CRC mortality by almost 50% by the Year 2020. However, without action now to further increase the uptake of current effective interventions, the reduction in CRC mortality may be only 17%. Cancer 2006. © American Cancer Society.

Objective: This study aimed at calculating and comparing the long-term outcomes of patients after aortic valve replacement with the Carpentier-Edwards bovine pericardial and porcine supraannular bioprostheses using microsimulation. Methods: We conducted a meta-analysis of eight studies on the Carpentier-Edwards pericardial valves (2685 patients, 12,250 patient-years) and five studies on the supraannular valves (3796 patients, 20,127 patient-years) to estimate the occurrence rates of valve-related events. Eighteen-year follow-up data sets were used to construct age-dependent Weibull curves that described their structural valvular deterioration. The estimates were entered into a microsimulation model, which was used to calculate the outcomes of patients after aortic valve replacement. Results: The annual hazard rates for thromboembolism after aortic valve replacement were 1.35% and 1.76% for the pericardial and supraannular valves, respectively. For a 65-year-old male, median time to structural valvular deterioration was 20.1 and 22.2 years while the lifetime risk of reoperation due to structural valvular deterioration was 18.3% and 14.0%, respectively. The life expectancy of the patient was 10.8 and 10.9 years and event-free life expectancy 9.0 and 8.8 years, respectively. Conclusions: The microsimulation methodology provides insight into the prognosis of a patient after aortic valve replacement with any given valve type. Both the Carpentier-Edwards pericardial and supraannular valve types perform satisfactorily, especially in elderly patients, and show no appreciable difference in long-term outcomes when implanted in the aortic position. # 2005 Elsevier B.V. All rights reserved.

Ivermectin and diethylcarbamazine (DEC) are used in mass treatment programs for the elimination of lymphatic filariasis because of their strong effects on microfilaremia. However, the effects of treatment on adult worms and the degree of individual variation in efficacy are unclear. We analyzed series of microfilaria (Mf) counts from individuals treated with a single dose of 400 microg/kg ivermectin or 6 mg/kg DEC (N = 23 in each group; 1 year follow-up). For each individual, we estimated the microfilaricidal effect and the reduction in overall Mf production (e.g., caused by death or sterilization of worms, or inhibited Mf release from the female worm uterus). Ivermectin on average killed 96% of Mf and reduced Mf production by 82%. DEC killed 57% of Mf and reduced Mf production by 67%, with some individuals responding very poorly. The strong reduction in overall Mf production is good news for control of lymphatic filariasis, but the prospects of elimination will be diminished if part of the population systematically responds poorly to treatment.

This observational study shows that the antral follicle count is a better predictor of ongoing pregnancy in IVF patients aged >38 years of age than is basal FSH. Patients aged

The early prediction of outcome after traumatic brain injury (TBI) is important for several purposes, but no prognostic models have yet been developed with proven generalizability across different settings. The objective of this study was to develop and validate prognostic models that use information available at admission to estimate 6-month outcome after severe or moderate TBI. To this end, this study evaluated mortality and unfavorable outcome, that is, death, and vegetative or severe disability on the Glasgow Outcome Scale (GOS), at 6 months post-injury. Prospectively collected data on 2269 patients from two multi-center clinical trials were used to develop prognostic models for each outcome with logistic regression analysis. We included seven predictive characteristics-age, motor score, pupillary reactivity, hypoxia, hypotension, computed tomography classification, and traumatic subarachnoid hemorrhage. The models were validated internally with bootstrapping techniques. External validity was determined in prospectively collected data from two relatively unselected surveys in Europe (n = 796) and in North America (n = 746). We evaluated the discriminative ability, that is, the ability to distinguish patients with different outcomes, with the area under the receiver operating characteristic curve (AUC). Further, we determined calibration, that is, agreement between predicted and observed outcome, with the Hosmer-Lemeshow goodness-of-fit test. The models discriminated well in the development population (AUC 0.78-0.80). External validity was even better (AUC 0.83-0.89). Calibration was less satisfactory, with poor external validity in the North American survey (p < 0.001). Especially, observed risks were higher than predicted for poor prognosis patients. A score chart was derived from the regression models to facilitate clinical application. Relatively simple prognostic models using baseline characteristics can accurately predict 6-month outcome in patients with severe or moderate TBI. The high discriminative ability indicates the potential of this model for classifying patients according to prognostic risk.

Background The second-generation Carpentier-Edwards pericardial valve (Edwards Lifesciences LLC, Irvine, CA) is widely used for aortic valve replacement. However, knowledge on the long-term outcomes of patients after valve implantation is incomplete. We used microsimulation to calculate the long-term outcome of any given patient after aortic valve replacement with the Carpentier-Edwards pericardial valve. Methods A meta-analysis of 8 reports on aortic valve replacement with the Carpentier-Edwards pericardial valve (2,685 patients; 12,250 patient years) was used to estimate the hazards of valve-related events other than structural valvular deterioration. Structural valvular deterioration was described by age-dependent Weibull curves calculated from 18-year follow-up, premarket approval, Carpentier-Edwards pericardial primary data. These estimates provided the input data for the parameters of the microsimulation model, which was then used to calculate the outcomes of patients of different ages after valve implantation. The model estimates of survival were validated using two external data sets. Results The Weibull analysis estimated a median time to reoperation for structural valvular deterioration ranging from 18.1 years for a 55-year-old male to 23.2 years for a 75-year-old male. For a 65-year-old male, microsimulation calculated a life expectancy and event-free life expectancy of 10.8 and 9.1 years, respectively. The lifetime risk of at least one valve-related event was 38% and that of reoperation due to structural valvular deterioration 17%, respectively, for this patient. The model estimates of survival showed good agreement with external data. Conclusions Microsimulation provides detailed insight into the long-term prognosis of patients after aortic valve replacement. The Carpentier-Edwards pericardial valve performs satisfactorily and offers a low lifetime risk of reoperation due to structural valvular deterioration, especially for elderly patients requiring aortic valve replacement.

Conventional treatment in normogonadotrophic anovulatory infertility (WHO 2) consists of clomiphene citrate (CC), followed by exogenous gonadotrophins (FSH) and IVF. Response to these treatments may be predicted on the basis of individual patient characteristics. We aimed to devise a patient-tailored, cost-effective treatment algorithm involving the above-mentioned treatment modalities, based on individual patient characteristics.Sixteen prognostic groups are defined, according to the presence or absence of: age30 years, amenorrhea, elevated androgen levels and obesity. The chances of response with each of the three treatments were calculated using prediction models. Treatment costs were based on the data of 240 patients visiting a specialist academic fertility unit. Outcome was an ongoing pregnancy within 12 months after initiation of treatment. The costs per pregnancy of three different strategies were compared, with a threshold for cost-effectiveness of 10 000.The strategy CC + FSH + IVF compared with FSH + IVF generated more pregnancies against lower costs. Compared with CC + IVF, it also produced more pregnancies, but at higher costs. For30 years of age with normal androgen levels, costs per pregnancy were less than 10 000. For women30 years old, costs per pregnancy were 25 000 and over 200 000, when presenting with normal or elevated androgen levels, respectively.The conventional treatment protocol is efficient for women aged30 years with normal androgen levels. For women30 years old with elevated androgen levels, FSH may be skipped.

BACKGROUND: Intrauterine insemination (IUI) can be performed with or without controlled ovarian hyperstimulation (COH). Studies in which the additional benefit of COH on IUI for cervical factor subfertility is assessed are lacking. We assessed whether COH in IUI improved pregnancy rates in cervical factor subfertility. METHODS: We performed a historical cohort study among couples with cervical factor subfertility, treated with IUI. A cervical factor was diagnosed by a well-timed, non-progressive post-coital test with normal semen parameters. We compared ongoing pregnancy rate per cycle in groups treated with IUI with or without COH. We tabulated ongoing pregnancy rates per cycle number and compared the effectiveness of COH by stratified univariable analysis. RESULTS: We included 181 couples who underwent 330 cycles without COH and 417 cycles with COH. Ongoing pregnancy rates in IUI cycles without and with COH were 9.7% and 12.7%, respectively (odds ratio 1.4; 95% confidence interval 0.85-2.2). The pregnancy rates in IUI without COH in cycles 1, 2, 3 and 4 were 14%, 11%, 6% and 15%, respectively. For IUI with COH, these rates were 17%, 15%, 14% and 16%, respectively. CONCLUSIONS: Although our data indicate that COH improves the pregnancy rate over IUI without COH, IUI without COH generates acceptable pregnancy rates in couples with cervical factor subfertility. Since IUI without COH bears no increased risk for multiple pregnancy, this treatment should be seriously considered in couples with cervical factor subfertility.

The use of the term 'infertility' and related terms in reproductive medicine is reviewed. Current terminology is found to be ambiguous, confusing, and misleading. We recommend that the fertility investigation report of a couple should consist of statements concerning description, diagnosis, and prognosis. The description concerns the duration of nonpregnancy before consulting the clinician. A system for prognostic grading is proposed. The fertility investigation report forms the basis for further action, including the possibility of waiting with treatment in case of almost normal or only slightly reduced fertility. The use of the terms 'infertility', 'subfertility', and 'fecundity' is not necessary, and it is recommended to avoid them.

Objective: To develop a prognostic model for the outcome of IUI. Design: Retrospective cohort study. Setting: Four fertility centers in The Netherlands. Patient(s): Couples of whom the female partners had a regular cycle and who had been treated with IUI. Intervention(s): Intrauterine insemination with and without ovarian hyperstimulation. Main Outcome Measure(s): Ongoing pregnancy. Result(s): Overall, 3,371 couples were included who underwent 14,968 cycles. There were 1,229 (8.2%) pregnancies, of which 1,000 (6.7%) pregnancies were ongoing. Logistic regression analysis demonstrated that increasing maternal age, longer duration of subfertility, presence of male factor subfertility, one-sided tubal pathology, endometriosis, uterine anomalies, and an increasing number of cycles were unfavorable predictors for an ongoing pregnancy. Cervical factor and the use of ovarian hyperstimulation were favorable predictors. The area under the receiver operating characteristic curve was 0.59. When couples were divided into four categories based on prognosis, the difference between the predicted and observed chance, that is, the calibration, was less than 0.5% in each of the four groups. Conclusion(s): Although our model had a relatively poor discriminative capacity, data on calibration showed that the selected prognostic factors allow distinction between couples with a poor prognosis and couples with a good prognosis. After external validation, this model could be of use in patient counseling and clinical decision making. (C) 2004 by American Society for Reproductive Medicine