Reactogenicity, pregnancy outcomes, and SARS-CoV-2 infection following COVID-19 vaccination during pregnancy in Canada: A national prospective cohort study.

OBJECTIVE: To describe self-reported reactogenicity, pregnancy outcomes, and SARS-CoV-2 infection following COVID-19 vaccination during pregnancy. DESIGN: National, prospective cohort study. SETTING: Participants across Canada were enrolled from July 2021 until June 2022. POPULATION: Individuals pregnant during the COVID-19 pandemic, regardless of vaccination status, were included. METHODS: The Canadian COVID-19 Vaccine Registry for Pregnant and Lactating Individuals (COVERED) was advertised through traditional and social media. Surveys were administered at baseline, following each vaccine dose if vaccinated, pregnancy conclusion, and every two months for 14 months. Changes to pregnancy or vaccination status, SARS-CoV-2 infections, or significant health events were recorded. MAIN OUTCOME MEASURES: Reactogenicity (local and systemic adverse events, and serious adverse events) within 1 week post-vaccination, pregnancy and neonatal outcomes, and subsequent SARS-CoV-2 infection. RESULTS: Among 2868 participants who received 1-2 doses of a COVID-19 vaccine during pregnancy, adverse events described included: headache (19.5-33.9%), nausea (4.8-13.8%), fever (2.7-10.2%), and myalgia (33.4-42.2%). Reactogenicity was highest after the 2nd dose of vaccine in pregnancy. Compared to 1660 unvaccinated participants, there were no statistically significant differences in adverse pregnancy or infant outcomes, aside from an increased risk of NICU admission ≥ 24 h among the unvaccinated group. During follow-up, there was a higher rate of participant-reported SARS-CoV-2 infection in the unvaccinated compared to the vaccinated group (18[47.4%] vs. 786[27.3%]). CONCLUSIONS: Participant-reported reactogenicity was similar to reports from non-pregnant adults. There was no increase in adverse pregnancy and birth outcomes among vaccinated vs. unvaccinated participants and lower rates of SARS-CoV-2 infection were reported in vaccinated participants. TWEETABLE ABSTRACT: No significant increase in adverse pregnancy or infant outcomes among vaccinated versus unvaccinated pregnant women in Canada.

CARTR Plus: the creation of an ART registry in Canada.

STUDY QUESTION: What is the status of fertility treatment and birth outcomes documented over the first 6 years of the Canadian Assisted Reproductive Technologies Register (CARTR) Plus registry? SUMMARY ANSWER: The CARTR Plus registry is a robust database containing comprehensive Canadian fertility treatment data to assist with providing evidence-based rationale for clinical practice change. WHAT IS KNOWN ALREADY: The rate of infertility is increasing globally and having data on fertility treatment cycles and outcomes at a population level is important for accurately documenting and effecting changes in clinical practice. STUDY DESIGN SIZE DURATION: This is a descriptive manuscript of 183 739 fertility treatment cycles from 36 Canadian clinics over 6 years from the CARTR Plus registry. PARTICIPANTS/MATERIALS SETTING METHODS: Canadian ART treatment cycles from 2013 through 2018 were included. This manuscript described trends in type of fertility treatment cycles, pregnancy rates, multiple pregnancy rates, primary transfer rates and birth outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Over the 6 years of the CARTR Plus registry, the number of treatment cycles performed ranged from less than 200 to greater than 1000 per clinic. Patient age and the underlying cause of infertility were two of the most variable characteristics across clinics. Similar clinical pregnancy rates were found among IVF and frozen embryo transfer (FET) cycles with own oocytes (38.9 and 39.7% per embryo transfer cycle, respectively). Fertility treatment cycles that used donor oocytes had a higher clinical pregnancy rate among IVF cycles compared with FET cycles (54.9 and 39.8% per embryo transfer cycle, respectively). The multiple pregnancy rate was 7.4% per ongoing clinical pregnancy in 2018, which reflected a decreasing trend across the study period. Between 2013 and 2017, there were 31 811 pregnancies that had live births from all ART treatment cycles, which corresponded to a live birth rate of 21.4% per cycle start and 89.1% of these pregnancies were singleton live births. The low multiple pregnancy rate and high singleton birth rate are associated with the increase in single embryo transfers. LIMITATIONS REASONS FOR CAUTION: There is potential for misclassification of data, which is present in all administrative health databases. WIDER IMPLICATIONS OF THE FINDINGS: The CARTR Plus registry is a robust resource for ART data in Canada. It provides easily accessible aggregated data for Canadian fertility clinics, and it contains data that are internationally comparable. STUDY FUNDING/COMPETING INTERESTS: There was no funding provided for this study. The authors have no competing interests to declare.

The Canadian Assisted Reproductive Technologies Register (CARTR) Plus database: a validation study.

STUDY QUESTION: Are data accurately documented in the Canadian Assisted Reproductive Technologies Register (CARTR) Plus database? SUMMARY ANSWER: Measures of validity were strong for the majority of variables evaluated while those with moderate agreement were FSH levels, oocyte origin and elective single embryo transfer. WHAT IS KNOWN ALREADY: Health databases and registries are excellent sources of data. However, as these databases are typically not established for the primary purpose of performing research, they should be evaluated prior to utilization for research both to inform the study design and to determine the extent to which key study variables, such as patient characteristics or therapies provided, are accurately documented in the database. CARTR Plus is Canada's national register for collecting extensive information on IVF and corresponding pregnancy outcomes, and it has yet to be validated. STUDY DESIGN SIZE DURATION: This study evaluating the data translation CARTR Plus database examined IVF cycles performed in 2015 using data directly from patient charts. Six clinics across Canada were recruited to participate, using a purposive sampling strategy. Fixed random sampling was employed to select 146 patient cycles at each clinic, representing unique patients. Only a single treatment cycle record from a unique patient at each clinic was considered during chart selection. PARTICIPANTS/MATERIALS SETTING METHODS: Twenty-five data elements (patient characteristics, treatments and outcomes) were reabstracted from patient charts, which were declared the reference standard. Data were reabstracted by two independent auditors with relevant clinical knowledge after confirming inter-rater reliability. These data elements from the chart were then compared to those in CARTR Plus. To determine the validity of these variables, we calculated kappa coefficients, sensitivity, specificity, positive predictive value and negative predictive value with 95% CI for categorical variables and calculated median differences and intraclass correlation coefficients (ICC) for continuous variables. MAIN RESULTS AND THE ROLE OF CHANCE: Six clinics agreed to participate in this study representing five Canadian provinces. The mean age of patients was 35.5 years, which was similar between the two data sources, resulting in a near perfect level of agreement (ICC = 0.99; 95% CI: 0.99, 0.99). The agreement for FSH was moderate, ICC = 0.68 (95% CI: 0.64, 0.72). There was nearly perfect agreement for cycle type, kappa = 0.99 (95% CI: 0.98, 1.00). Over 90% of the cycles in the reabstracted charts used autologous oocytes; however, data on oocyte source were missing for 13% of cycles in CARTR Plus, resulting in a moderate degree of agreement, kappa = 0.45 (95% CI, 0.37, 0.52). Embryo transfer and number of embryos transferred had nearly perfect agreement, with kappa coefficients greater than 0.90, whereas that for elective single or double embryo transfer was much lower (kappa = 0.55; 95% CI: 0.49, 0.61). Agreement was nearly perfect for pregnancy type, and number of fetal sacs and fetal hearts on ultrasound, all with kappa coefficients greater than 0.90. LARGE-SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: CARTR Plus contains over 200 variables, of which only 25 were assessed in this study. This foundational validation work should be extended to other CARTR Plus database variables in future studies. WIDER IMPLICATIONS OF THE FINDINGS: This study provides the first assessment of the quality of the data translation process of the CARTR Plus database, and we found very high quality for the majority of the variables that were analyzed. We identified key data points that are either too often lacking or inconsistent with chart data, indicating that changes in the data entry process may be required. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Canadian Institutes of Health Research (CIHR) (Grant Number FDN-148438) and by the Canadian Fertility and Andrology Society Research Seed Grant (Grant Number: N/A). The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

A systematic review of database validation studies among fertility populations.

STUDY QUESTION: Are routinely collected data from fertility populations adequately validated? SUMMARY ANSWER: Of the 19 studies included, only one validated a national fertility registry and none reported their results in accordance with recommended reporting guidelines for validation studies. WHAT IS KNOWN ALREADY: Routinely collected data, including administrative databases and registries, are excellent sources of data, particularly for reporting, quality assurance, and research. However, these data are subject to misclassification bias due to misdiagnosis or errors in data entry and therefore need to be validated prior to using for clinical or research purposes. STUDY DESIGN SIZE DURATION: We conducted a systematic review by searching Medline, Embase, and CINAHL from inception to 6 October 2016 to identify validation studies of databases that contain routinely collected data in an ART setting. Webpages of international ART centers were also searched. PARTICIPANTS/MATERIALS SETTING METHODS: We included studies that compared at least two data sources to validate ART population data. Key words and MeSH terms were adapted from previous systematic reviews investigating routinely collected data (e.g. administrative databases and registries), measures of validity (including sensitivity, specificity, and predictive value), and ART (including infertility, IVF, advanced reproductive age, and diminished ovarian reserve). Only full-text studies in English were considered. Results were synthesized qualitatively. The electronic search yielded 1074 citations, of which 19 met the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Two studies validated a fertility database using medical records; seven studies used an IVF registry to validate vital records or maternal questionnaires, and two studies failed to adequately describe their reference standard. Four studies investigated the validity of mode of conception from birth registries; two studies validated diagnoses or treatments in a fertility database; four studies validated a linkage algorithm between a fertility registry and another administrative database; one study created an algorithm in a single database to identify a patient population. Sensitivity was the most commonly reported measure of validity (12 studies), followed by specificity (9 studies). Only three studies reported four or more measures of validation, and five studies presented CIs for their estimates. The prevalence of the variable in the target population (pre-test prevalence) was reported in seven studies; however, only four of the studies had prevalence estimates from the study population (post-test prevalence) within a 2% range of the pre-test estimate. The post-test estimate was largely discrepant from the pre-test value in two studies. LIMITATIONS REASONS FOR CAUTION: The search strategy was limited to the studies and reports published in English, which may not capture validation studies from countries that do not speak English. Furthermore, only three specific fertility-based diagnostic variables (advanced reproductive age, diminished ovarian reserve, and chorionicity) were searched in Medline, Embase, and CINAHL. Consequently, published studies with other diagnoses or conditions relevant to infertility may not have been captured in our review. WIDER IMPLICATIONS OF THE FINDINGS: There is a paucity of literature on validation of routinely collected data from a fertility population. Furthermore, the prevalence of the markers that have been validated are not being presented, which can lead to biased estimates. Stakeholders rely on these data for monitoring outcomes of treatments and adverse events; therefore, it is essential to ascertain the accuracy of these databases and make the reports publicly available. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Canadian Institutes of Health Research (CIHR) (FDN-148438). There are no competing interests for any of the authors. REGISTRATION NUMBER: International Prospective Register of Systematic Reviews ID: CRD42016048466.

The transplacental passage of commonly used intrapartum antibiotics and its impact on the newborn management: A narrative review.

Neonates exposed to intra-amniotic infection are at increased risk of early-onset sepsis. Administration of antibiotics to the mother may offer some protection, however a comprehensive description of the determinants influencing their transplacental passage and delivery to the fetus has not been performed. While penicillin G, ampicillin, cefazolin and gentamicin reach therapeutic levels in the fetal serum rapidly following maternal administration, the transfer of second-line intrapartum antimicrobials, such as vancomycin and clindamycin, is slower and less predictable. Erythromycin, used in the context of preterm premature rupture of the membranes, has suboptimal influx into the fetal compartment. This evidence is predominantly drawn from term pregnancies and situations of low infectious risk; however, prematurity may negatively influence fetal exposure to intrapartum antibiotics. Optimal fetal antimicrobial concentrations to target are poorly defined and the extent to which our review findings apply to preterm early-onset neonatal sepsis prevention is unclear. Interpretation of blood cultures drawn in neonates with expected circulating levels of maternal antimicrobials above the minimal inhibitory concentration for Group B Streptococcus is challenging despite the use of contemporary optimized blood culture media.

Severe maternal morbidity in women with high BMI in IVF and unassisted singleton pregnancies.

STUDY QUESTION: Is there a synergistic risk of severe maternal morbidity (SMM) in overweight/obese women who conceived by IVF compared to normal-weight women without IVF? SUMMARY ANSWER: SMM was more common in IVF pregnancies, and among overweight/obese women, but we did not detect a synergistic effect of both factors. WHAT IS KNOWN ALREADY: While much is known about the impact of overweight and obesity on success rates after IVF, there is less data on maternal health outcomes. STUDY DESIGN, SIZE, DURATION: This is a population-based cohort study of 114 409 singleton pregnancies with conceptions dating from 11 January 2013 until 10 January 2014 in Ontario, Canada. The data source was the Canadian Assisted Reproductive Technologies Register (CARTR Plus) linked with the Ontario birth registry (BORN Information System). PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women who delivered at ≥20 weeks gestation, and excluded those younger than 18 years or with twin pregnancies. Women were classified according to the mode of conception (IVF or unassisted) and according to pre-pregnancy BMI (high BMI (≥25 kg/m2) or low-normal BMI (<25 kg/m2)). The main outcome was SMM, a composite of serious complications using International Classification of Diseases, 10th revision (ICD-10) codes. Secondary outcomes were gestational hypertension, pre-eclampsia, gestational diabetes and cesarean delivery. Adjusted risk ratios (aRR) with 95% CI were estimated using log binomial regression, adjusted for maternal age, parity, education, income and baseline maternal comorbidity. MAIN RESULTS AND THE ROLE OF CHANCE: Of 114 409 pregnancies, 1596 (1.4%) were IVF conceptions. Overall, 41.2% of the sample had high BMI, which was similar in IVF and non-IVF groups. We observed 674 SMM events (rate: 5.9 per 1000 deliveries). IVF was associated with an increased risk of SMM (rate 11.3/1000; aRR 1.89, 95% CI: 1.06-3.39). High BMI was modestly associated with SMM (rate 7.0/1000; aRR 1.23, 95% CI: 1.04-1.45) There was no interaction between the two factors (P = 0.22). We noted supra-additive effects of high BMI and IVF on the risk of pre-eclampsia and gestational diabetes, but not gestational hypertension or cesarean delivery. LIMITATIONS, REASONS FOR CAUTION: We were unable to assess outcomes according to reason for treatment. Type II error (beta ~25%) may affect our results. WIDER IMPLICATIONS OF THE FINDINGS: Our results support previous data indicating a greater risk of SMM in IVF pregnancies, and among women with high BMI. However, these factors do not interact. Overweight and obese women who seek treatment with IVF should be counseled about pregnancy risks. The decision to proceed with IVF should be based on clinical judgment after considering an individual's chance of success and risk of complications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Research Institute of the McGill University Health Centre (grant 6291) and also supported by the Trio Fertility (formerly Lifequest) Research Fund. The authors report no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Model-based biotechnological potential analysis of Kluyveromyces marxianus central metabolism.

The non-conventional yeast Kluyveromyces marxianus is an emerging industrial producer for many biotechnological processes. Here, we show the application of a biomass-linked stoichiometric model of central metabolism that is experimentally validated, and mass and charge balanced for assessing the carbon conversion efficiency of wild type and modified K. marxianus. Pairs of substrates (lactose, glucose, inulin, xylose) and products (ethanol, acetate, lactate, glycerol, ethyl acetate, succinate, glutamate, phenylethanol and phenylalanine) are examined by various modelling and optimisation methods. Our model reveals the organism's potential for industrial application and metabolic engineering. Modelling results imply that the aeration regime can be used as a tool to optimise product yield and flux distribution in K. marxianus. Also rebalancing NADH and NADPH utilisation can be used to improve the efficiency of substrate conversion. Xylose is identified as a biotechnologically promising substrate for K. marxianus.

Maternal influenza and birth outcomes: systematic review of comparative studies.

BACKGROUND: Although pregnant women are considered at high risk for severe influenza disease, comparative studies of maternal influenza and birth outcomes have not been comprehensively summarised. OBJECTIVE: To review comparative studies evaluating maternal influenza disease and birth outcomes. SEARCH STRATEGY: We searched bibliographic databases from inception to December 2014. SELECTION CRITERIA: Studies of preterm birth, small-for-gestational-age (SGA) birth or fetal death, comparing women with and without clinical influenza illness or laboratory-confirmed influenza infection during pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: Heterogeneity across 16 studies reporting preterm birth precluded meta-analysis. In a subgroup of the highest-quality studies, two reported significantly increased preterm birth (risk ratios (RR) from 2.4 to 4.0) following severe 2009 pandemic H1N1 (pH1N1) influenza illness, whereas those assessing mild-to-moderate pH1N1 or seasonal influenza found no association. Five studies of SGA birth showed no discernible patterns with respect to influenza disease severity (pooled odds ratio 1.24; 95% CI 0.96-1.59). Two fetal death studies were of sufficient quality and size to permit meaningful interpretation. Both reported an increased risk of fetal death following maternal pH1N1 disease (RR 1.9 for mild-to-moderate disease and 4.2 for severe disease). CONCLUSIONS: Comparative studies of preterm birth, SGA birth and fetal death following maternal influenza disease are limited in number and quality. An association between severe pH1N1 disease and preterm birth and fetal death was reported by several studies; however, these limited data do not permit firm conclusions on the magnitude of any association. TWEETABLE ABSTRACT: Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth.

Fetal death and preterm birth associated with maternal influenza vaccination: systematic review.

BACKGROUND: Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently. OBJECTIVES: To review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. SEARCH STRATEGY: We searched bibliographic databases from inception to April 2014. SELECTION CRITERIA: Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data from studies meeting the inclusion criteria. MAIN RESULTS: We included one randomised clinical trial and 26 observational studies. Meta-analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56-0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at ≥20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non-significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta-regression did not explain the moderate between-study heterogeneity (I(2) = 57%). AUTHORS' CONCLUSIONS: Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness.

Antiviral medication use in a cohort of pregnant women during the 2009-2010 influenza pandemic.

Preventing influenza-like illness (ILI) during pregnancy with antiviral medication use (AVMU) can mitigate serious health risks to mother and foetus. We report on AVMU in pregnant women in Ontario, Canada, and describe characteristics of AVMU during the 2009-2010 H1N1 pandemic. Rates and risk estimates of AVMU were compared across multiple categories and stratified across ILI infection status. Increased AVMU was observed in women with influenza infections, active smokers, those vaccinated against influenza, and those with pre-existing co-morbidities. Decreased AVMU was observed in women with multiple gestations, and those in neighbourhoods of high immigrant concentrations. Our stratified analysis indicated that the observed patterns differed by ILI infection status. We demonstrated that once infected, women across multiple groups were equally likely to use antiviral medications. In this report we also propose possible clinical explanations for the observed differences in AVMU, which will be useful in planning prevention initiatives for future pandemics.

Measuring contact angle and meniscus shape with a reflected laser beam.

Side-view imaging of the contact angle between an extended planar solid surface and a liquid is problematic. Even when aligning the view perfectly parallel to the contact line, focusing one point of the contact line is not possible. We describe a new measurement technique for determining contact angles with the reflection of a widened laser sheet on a moving contact line. We verified this new technique measuring the contact angle on a cylinder, rotating partially immersed in a liquid. A laser sheet is inclined under an angle φ to the unperturbed liquid surface and is reflected off the meniscus. Collected on a screen, the reflection image contains information to determine the contact angle. When dividing the laser sheet into an array of laser rays by placing a mesh into the beam path, the shape of the meniscus can be reconstructed from the reflection image. We verified the method by measuring the receding contact angle versus speed for aqueous cetyltrimethyl ammonium bromide solutions on a smooth hydrophobized as well as on a rough polystyrene surface.

Evaluation of the impact of fetal fibronectin test implementation on hospital admissions for preterm labour in Ontario: a multiple baseline time-series design.

OBJECTIVE: To determine the impact of a health system-wide fetal fibronectin (fFN) testing programme on the rates of hospital admission for preterm labour (PTL). DESIGN: Multiple baseline time-series design. SETTING: Canadian province of Ontario. POPULATION: A retrospective population-based cohort of antepartum and delivered obstetrical admissions in all Ontario hospitals between 1 April 2002 and 31 March 2010. METHODS: International Classification of Diseases codes in a health system-wide hospital administrative database were used to identify the study population and define the outcome measure. An aggregate time series of monthly rates of hospital admissions for PTL was analysed using segmented regression models after aligning the fFN test implementation date for each institution. MAIN OUTCOME MEASURE: Rate of obstetrical hospital admission for PTL. RESULTS: Estimated rates of hospital admission for PTL following fFN implementation were lower than predicted had pre-implementation trends prevailed. The reduction in the rate was modest, but statistically significant, when estimated at 12 months following fFN implementation (-0.96 hospital admissions for PTL per 100 preterm births; 95% confidence interval [CI], -1.02 to -0.90, P = 0.04). The statistically significant reduction was sustained at 24 and 36 months following implementation. CONCLUSIONS: Using a robust quasi-experimental study design to overcome confounding as a result of underlying secular trends or concurrent interventions, we found evidence of a small but statistically significant reduction in the health system-level rate of hospital admissions for PTL following implementation of fFN testing in a large Canadian province.

Validity of autism diagnoses using administrative health data.

It is necessary to monitor autism prevalence in order to plan education support and health services for affected children. This study was conducted to assess the accuracy of administrative health databases for autism diagnoses. Three administrative health databases from the province of Nova Scotia were used to identify diagnoses of autism spectrum disorders (ASD): the Hospital Discharge Abstract Database, the Medical Services Insurance Physician Billings Database and the Mental Health Outpatient Information System database. Seven algorithms were derived from combinations of requirements for single or multiple ASD claims from one or more of the three administrative databases. Diagnoses made by the Autism Team of the IWK Health Centre, using state-of-the-art autism diagnostic schedules, were compared with each algorithm, and the sensitivity, specificity and C-statistic (i.e. a measure of the discrimination ability of the model) were calculated. The algorithm with the best test characteristics was based on one ASD code in any of the three databases (sensitivity=69.3%). Sensitivity based on an ASD code in either the hospital or the physician billing databases was 62.5%. Administrative health databases are potentially a cost efficient source for conducting autism surveillance, especially when compared to methods involving the collection of new data. However, additional data sources are needed to improve the sensitivity and accuracy of identifying autism in Canada.

SysBioMed report: advancing systems biology for medical applications.

The following report selects and summarises some of the conclusions and recommendations generated throughout a series of workshops and discussions that have lead to the publication of the Science Policy Briefing (SPB) Nr. 35, published by the European Science Foundation. (Large parts of the present text are directly based on the ESF SPB. Detailed recommendations with regard to specific application areas are not given here but can be found in the SPB. Issues related to mathematical modelling, including training and the need for an infrastructure supporting modelling are discussed in greater detail in the present text.)The numerous reports and publications about the advances within the rapidly growing field of systems biology have led to a plethora of alternative definitions for key concepts. Here, with 'mathematical modelling' the authors refer to the modelling and simulation of subcellular, cellular and macro-scale phenomena, using primarily methods from dynamical systems theory. The aim of such models is encoding and testing hypotheses about mechanisms underlying the functioning of cells. Typical examples are models for molecular networks, where the behaviour of cells is expressed in terms of quantitative changes in the levels of transcripts and gene products. Bioinformatics provides essential complementary tools, including procedures for pattern recognition, machine learning, statistical modelling (testing for differences, searching for associations and correlations) and secondary data extracted from databases.Dynamical systems theory is the natural language to investigate complex biological systems demonstrating nonlinear spatio-temporal behaviour. However, the generation of experimental data suitable to parameterise, calibrate and validate such models is often time consuming and expensive or not even possible with the technology available today. In our report, we use the term 'computational model' when mathematical models are complemented with information generated from bioinformatics resources. Hence, 'the model' is, in reality, an integrated collection of data and models from various (possibly heterogeneous) sources. The present report focuses on a selection of topics, which were identified as appropriate case studies for medical systems biology, and adopts a particular perspective which the authors consider important. We strongly believe that mathematical modelling represents a natural language with which to integrate data at various levels and, in doing so, to provide insight into complex diseases: 1. Modelling necessitates the statement of explicit hypotheses, a process which often enhances comprehension of the biological system and can uncover critical points where understanding is lacking. 2. Simulations can reveal hidden patterns and/or counter-intuitive mechanisms in complex systems. 3. Theoretical thinking and mathematical modelling constitute powerful tools to integrate and make sense of the biological and clinical information being generated and, more importantly, to generate new hypotheses that can then be tested in the laboratory.Medical Systems Biology projects carried out recently across Europe have revealed a need for action: 4. While the need for mathematical modelling and interdisciplinary collaborations is becoming widely recognised in the biological sciences, with substantial implications for the training and research funding mechanisms within this area, the medical sciences have yet to follow this lead. 5. To achieve major breakthroughs in Medical Systems Biology, existing academic funding schemes for large-scale projects need to be reconsidered. 6. The hesitant stance of the pharmaceutical industry towards major investment in systems biology research has to be addressed. 7. Leading medical journals should be encouraged to promote mathematical modelling.

Challenges to be faced in the reconstruction of metabolic networks from public databases.

In the post-genomic era, the biochemical information for individual compounds, enzymes, reactions to be found within named organisms has become readily available. The well-known KEGG and BioCyc databases provide a comprehensive catalogue for this information and have thereby substantially aided the scientific community. Using these databases, the complement of enzymes present in a given organism can be determined and, in principle, used to reconstruct the metabolic network. However, such reconstructed networks contain numerous properties contradicting biological expectation. The metabolic networks for a number of organisms are reconstructed from KEGG and BioCyc databases, and features of these networks are related to properties of their originating database.

Using a mammalian cell cycle simulation to interpret differential kinase inhibition in anti-tumour pharmaceutical development.

Systems biology needs to show practical relevance to commercial biological challenges such as those of pharmaceutical development. The aim of this work is to design and validate some applications in anti-cancer therapeutic development. The test system was a group of novel cyclin-dependent kinase (CDK) inhibitors synthesised by Cyclacel Ltd. The measured in vitro IC50s of each compound were used as input data to a proprietary cell cycle model developed by Physiomics plc. The model was able to predict over three orders of magnitude the cytotoxicity of each compound without model adaptation to specific cancer cell types. This pattern matched the experimentally determined data. One class of compounds was predicted to cause an increase of the cell cycle length with a non-linear dose-response curve. Further work will use apoptosis and DNA replication simulations to look at overall cell effects.

Haloacetic acids in drinking water and risk for stillbirth.

BACKGROUND: Trihalomethanes (THMs) occurring in public drinking water sources have been investigated in several epidemiological studies of fetal death and results support a modest association. Other classes of disinfection by-products found in drinking water have not been investigated. AIMS: To investigate the effects of haloacetic acid (HAA) compounds in drinking water on stillbirth risk. METHODS: A population based case-control study was conducted in Nova Scotia and Eastern Ontario, Canada. Estimates of daily exposure to total and specific HAAs were based on household water samples and questionnaire information on water consumption at home and work. RESULTS: The analysis included 112 stillbirth cases and 398 live birth controls. In analysis without adjustment for total THM exposure, a relative risk greater than 2 was observed for an intermediate exposure category for total HAA and dichloroacetic acid measures. After adjustment for total THM exposure, the risk estimates for intermediate exposure categories were diminished, the relative risk associated with the highest category was in the direction of a protective effect, and all confidence intervals included the null value. CONCLUSIONS: No association was observed between HAA exposures and stillbirth risk after controlling for THM exposures.

A method for the determination of flux in elementary modes, and its application to Lactobacillus rhamnosus.

In this article we address the question of how, given information about the reaction fluxes of a system, flux values can be assigned to the elementary modes of that system. Having described a method by which this may be accomplished, we first illustrate its application to a hypothetical, in silico system, and then apply it to fermentation data from Lactobacillus rhamnosus. This reveals substantial changes in the flux values assigned to elementary modes, and thus to the internal metabolism, as the fermentation progresses. This is information that could not, to our knowledge, be obtained by existing methods. The relationship between our technique and the well-known method of Metabolic Flux Analysis is also discussed.