Spatial distribution of clinical computer systems in primary care in England in 2016 and implications for primary care electronic medical record databases: a cross-sectional population study.

OBJECTIVES: UK primary care databases (PCDs) are used by researchers worldwide to inform clinical practice. These databases have been primarily tied to single clinical computer systems, but little is known about the adoption of these systems by primary care practices or their geographical representativeness. We explore the spatial distribution of clinical computing systems and discuss the implications for the longevity and regional representativeness of these resources. DESIGN: Cross-sectional study. SETTING: English primary care clinical computer systems. PARTICIPANTS: 7526 general practices in August 2016. METHODS: Spatial mapping of family practices in England in 2016 by clinical computer system at two geographical levels, the lower Clinical Commissioning Group (CCG, 209 units) and the higher National Health Service regions (14 units). Data for practices included numbers of doctors, nurses and patients, and area deprivation. RESULTS: Of 7526 practices, Egton Medical Information Systems (EMIS) was used in 4199 (56%), SystmOne in 2552 (34%) and Vision in 636 (9%). Great regional variability was observed for all systems, with EMIS having a stronger presence in the West of England, London and the South; SystmOne in the East and some regions in the South; and Vision in London, the South, Greater Manchester and Birmingham. CONCLUSIONS: PCDs based on single clinical computer systems are geographically clustered in England. For example, Clinical Practice Research Datalink and The Health Improvement Network, the most popular primary care databases in terms of research outputs, are based on the Vision clinical computer system, used by <10% of practices and heavily concentrated in three major conurbations and the South. Researchers need to be aware of the analytical challenges posed by clustering, and barriers to accessing alternative PCDs need to be removed.

Airway epithelial cytokine responses in childhood wheeze are independent of atopic status.

BACKGROUND: Airway epithelial cells (AEC) are key contributors to immune function in the lungs but little is known about their role and function in children. OBJECTIVES: Having previously established that nasal AEC mediator release correlates with that of bronchial AEC, we assessed AEC responses in children with and without a history of wheeze. METHODS: Nasal AEC cultures were established from children (0.6-14.9 years) undergoing elective surgical procedures under general anaesthetic categorised as atopic asthmatic (n = 12), virus-induced wheeze (n = 8) or children without wheeze (n = 32). Mediator release by AEC monolayers at passage 2 was determined by cytometric bead array assay or ELISA. RESULTS: Unstimulated AEC from children with a history of wheeze produced significantly less IL-8, IL-6, MCP-1 and G-CSF than AEC from healthy controls. There were no group differences in AEC release of VEGF, RANTES, MMP-9 or TIMP-1. After stimulation with the pro-inflammatory cytokines IL-1ß and TNFα, AEC from children with current wheeze produced significantly less IL-8, IL-6 and MCP-1 than children without wheeze. Release of G-CSF, VEGF, MMP-9 and TIMP-1 did not differ between the wheeze and control group. There were no differences in mediator release between subjects with atopic asthma and those with virus-induced wheeze or between atopic and non-atopic controls. On multivariate analysis, wheeze was the only significant predictor of AEC mediator release. CONCLUSION & CLINICAL RELEVANCE: Intrinsic differences in AEC from children with a history of wheeze may reflect a defect in cytokine production in vivo or an altered state of differentiation in vitro, independent of atopic status.

Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review.

AIMS: A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children. METHODS: MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed. RESULTS: From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants. CONCLUSIONS: Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base.

Maternal vitamin D and E intakes during pregnancy are associated with asthma in children.

Are maternal vitamin D and E intakes during pregnancy associated with asthma in 10-year-old children? In a longitudinal study of 1924 children born to women recruited during pregnancy, maternal vitamin D intake during pregnancy was assessed by the Food Frequency Questionnaire (FFQ) and vitamin E by FFQ and plasma α-tocopherol; respiratory questionnaires were completed for the 10-year-old children. Their treatment for asthma was also ascertained using administrative data. Longitudinal analyses included data collected at 1, 2, 5 and 10 years. Symptom data were available for 934 (49%) children and use of asthma medication for 1748 (91%). In the children maternal vitamin D intake during pregnancy was negatively associated with doctor-diagnosed asthma at 10 years of age (OR per intake quintile 0.86, 95% CI 0.74-0.99) and over the first 10 years (hazard ratio 0.90, 95% CI 0.81-1.00). Maternal plasma α-tocopherol at 11 weeks gestation was negatively associated with children receiving asthma treatment (OR per standard deviation increase 0.52, 95% CI 0.31-0.87). Maternal vitamin E intake was negatively associated with doctor-diagnosed asthma (OR 0.89, 95% CI 0.81-0.99) in the first 10 years. Low maternal vitamin D and E intakes during pregnancy are associated with increased risk of children developing asthma in the first 10 years of life. These associations may have significant public health implications.

'The more you link, the more you risk ' - a focus group study exploring views about data linkage for pharmacovigilance.

AIMS: The aim of this study was to assess opinions of frontline healthcare professionals on the linking of routinely collected national (Scottish) paediatric data for the purpose of identifying earlier signals of adverse drug reactions. METHODS: Stratified purposive sampling led to profession-specific focus groups with pharmacists, nurses and medical doctors from primary and secondary care in different Scottish Health Boards. A topic guide was used to explore the proposed data linkage of routinely collected paediatric data. Discussions were audio recorded and transcribed verbatim. Transcripts were analysed using a framework approach to identify themes. Ethical approval was obtained from the North of Scotland Research Ethics Service. RESULTS: Six focus groups were conducted in 2011 with 22 participants. Views of the proposed data linkage were generally positive. Several issues were identified, including lack of clarity on data ownership and concerns about diversion of funding. Identified issues were at a practical rather than a strategic level. CONCLUSIONS: This study identified that professional stakeholder groups are likely to find linkage of paediatric patient data acceptable. Barriers identified could be addressed. Focus group participants commented on the importance of informing patients and members of the public about the benefits of linking healthcare data. These findings clarify the steps that should be taken to ensure the acceptability of data linkage for pharmacovigilance.

Unplanned medication discontinuation as a potential pharmacovigilance signal: a nested young person cohort study.

BACKGROUND: Because of relatively small treatment numbers together with low adverse drug reaction (ADR) reporting rates the timely identification of ADRs affecting children and young people is problematic. The primary objective of this study was to assess the utility of unplanned medication discontinuation as a signal for possible ADRs in children and young people. METHODS: Using orlistat as an exemplar, all orlistat prescriptions issued to patients up to 18 years of age together with patient characteristics, prescription duration, co-prescribed medicines and recorded clinical (Read) codes were identified from the Primary Care Informatics Unit database between 1st Jan 2006-30th Nov 2009. Binary logistic regression was used to assess association between characteristics and discontinuation. RESULTS: During the study period, 79 patients were prescribed orlistat (81% female, median age 17 years). Unplanned medication discontinuation rates for orlistat were 52% and 77% at 1 and 3-months. Almost 20% of patients were co-prescribed an anti-depressant. One month unplanned medication discontinuation was significantly lower in the least deprived group (SIMD 1-2 compared to SIMD 9-10 OR 0.09 (95% CI0.01 - 0.83)) and those co-prescribed at least one other medication. At 3 months, discontinuation was higher in young people (≥17 yr versus, OR 3.07 (95% CI1.03 - 9.14)). Read codes were recorded for digestive, respiratory and urinary symptoms around the time of discontinuation for 24% of patients. Urinary retention was reported for 7.6% of patients. CONCLUSIONS: Identification of unplanned medication discontinuation using large primary care datasets may be a useful tool for pharmacovigilance signal generation and detection of potential ADRs in children and young people.

Linked health data for pharmacovigilance in children: perceived legal and ethical issues for stakeholders and data guardians.

OBJECTIVE: The inclusion of the Community Health Index in the recording of National Health Service (NHS) contacts in Scotland facilitates national linkage of data such as prescribing and healthcare utilisation. This linkage could be the basis for identification of adverse drug reactions. The aim of this article is to report the views of healthcare professionals on data sharing, ownership and the legal and other applicable frameworks relevant to linkage of routinely collected paediatric healthcare data. DESIGN: Qualitative study using semistructured face-to-face interviews addressing the study aims. PARTICIPANTS: Purposive sample of professional stakeholders (n=25) including experts on ethics, data protection, pharmacovigilance, data linkage, legal issues and prescribing. Interviews were audio-recorded, transcribed and thematically analysed using a framework approach. RESULTS: Participants identified existing data sharing systems in the UK. Access to healthcare data should be approved by the data owners. The definition of data ownership and associated legal responsibilities for linked healthcare data were seen as important factors to ensure accountability for the use of linked data. Yet data owners were seen as facilitators of the proposed data linkage. Twelve frameworks (legal, regulatory and governance) applicable to the linkage of healthcare data were identified. CONCLUSIONS: A large number of potentially relevant legal and regulatory frameworks were identified. Ownership of the linked data was seen as an extension of responsibility for, or guardianship of, the source datasets. The consensus emerging from the present study was that clarity is required on the definition of data sharing, data ownership and responsibilities of data owners.

Development of an enantiomer selective microsampling assay for the quantification of ketorolac suitable for paediatric pharmacokinetic studies.

BACKGROUND: Ketorolac, a potent nonsteroidal anti-inflammatory drug used for pain control in children, exists as a racemate of inactive R (+) and active S (-) enantiomers. AIM: To develop a microsampling assay for the enantioselective analysis of ketorolac in children. METHODS: Ketorolac enantiomers were extracted from 50 µl of plasma by liquid­liquid extraction and separated on a ChiralPak AD-RH. Detection was by a TSQ quantum triple quadrupole mass spectrometer with an electrospray ionisation source operating in a positive ion mode. Five children (age 13.8 (1.6) years, weight 52.7 (7.2) kg), were administered intravenous ketorolac 0.5mg/kg (maximum 10mg) and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h post administration. CL, VD and t1/2 were calculated based on non-compartmental methods. RESULTS: The standard curves for R (+) and S (-) ketorolac were linear in the range 0­2000 ng/ml. The LLOQs of the method were 0.15 ng on column and 0.31 ng on column for R (+) and S (-) ketorolac, respectively. The median (range) VD and CL of R (+) and S (-) ketorolac were 0.12 l/kg (0.07­0.17), 0.017 l/h/kg (0.12­0.29) and 0.17 (0.09­0.31) l/kg, 0.049 (0.02­0.1) l/h/kg, p = 0.043), respectively. The median (range) elimination half-life (t1/2) of the R (+) and S (-) ketorolac was 5.0 h (2.5­5.8) and 3.1 h (1.8­4.4), p = 0.043), respectively. CONCLUSION: The development of a simple, rapid and reliable ketorolac assay suitable for paediatric PK studies is reported.

Adequate levels of adherence with controller medication is associated with increased use of rescue medication in asthmatic children.

BACKGROUND: The role of asthma controller medication adherence and the level of asthma control in children is poorly defined. AIMS: To assess the association between asthma controller medication adherence and asthma control in children using routinely acquired prescribing data. METHODS: A retrospective observational study of children aged 0-18 years prescribed inhaled corticosteroids only (ICS), leukotriene receptors antagonists (LTRA), or long-acting ß2 agonists (LABA) and ICS prescribed as separate or combined inhalers, between 01/09/2001 and 31/08/2006, registered with primary care practices contributing to the Practice Team Information database. The medication possession ratio (MPR) was calculated and associations with asthma control explored. Poor asthma control was defined as the issue of prescriptions for ≥ 1 course of oral corticosteroids (OCS) and/or ≥ 6 short-acting ß2 agonists (SABA) canisters annually. RESULTS: A total of 3172 children prescribed asthma controller medication were identified. Of these, 15-39% (depending on controller medication) demonstrated adequate MPR. Adequate MPR was associated with male gender, good socio-economic status, and oral LTRA therapy. Adequate MPR was more likely to be associated with increased use of rescue medication. However logistic regression only identified a significant relationship for ICS only (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.35-2.48; p<0.001), LTRA (OR, 2.11; 95% CI, 1.27-3.48; p = 0.004) and LABA/ICS (OR, 2.85; 95% CI, 1.62-5.02; p<0.001). CONCLUSION: Poor adherence was observed for all asthma controller medications, although was significantly better for oral LRTA. In this study adequate adherence was not associated with the use of less rescue medication, suggesting that adherence is a complex issue.

Using primary care prescribing databases to determine drug switching and continuation of care.

Drug switching is a common medical practice. It indicates continuation of treatment regardless of the reason why the original therapy was stopped and switched. Therefore, the aims of this study were to develop a novel method for determining drug switching from routinely acquired NHS health data and to explore the aspect of continuation of care for patients. Patients who were first prescribed ramipril, simvastatin and an angiotensin receptor blocker (ARB) between 1 March 2004 and 28 February 2007 and discontinued their medication within 6 months of the index prescription were identified from the PTI database. The identified patients were then categorized into three groups: i) patients who were switched to a different drug for the same medical condition, ii) patients who were being prescribed with other types of antihypertensive/lipid-regulating drug prior to the initiation of study; and iii) patients who were without any continuation of care or therapy. Twenty percent (808), 29%(1429) and 14%(455) of the identified patients discontinued ramipril, simvastatin and ARB, respectively, within 6 months of an index prescription. Among the ramipril discontinuation group, 36.4% of the patients were switched to another antihypertensive, while another 31.6% of them were without continuation of care. In patients discontinuing ARB, 30.6% were switched, while another 30.1% were without continuation of treatment. In patients discontinuing simvastatin, 28.8% were switched to another lipid-regulating medicine, while another 63.1% of them were without continuation of care. The results of this study confirm that primary care prescribing databases can be used to determine drug-switching information and continuation of care/therapy.

Changes in primary care prescribing patterns for paediatric asthma: a prescribing database analysis.

BACKGROUND: Little is known about the impact of British asthma management guideline revisions. Concerns about the use of high dose inhaled corticosteroids (ICS) in children have resulted in the promotion of add-on therapy. AIMS: To assess prescribing patterns of asthma medication in children in the primary care setting. METHODS: Retrospective observational study of asthma prescribing in children aged 0-18 years using primary care database from 2001 to 2006. RESULTS: The proportion of children prescribed oral corticosteroids increased significantly (from 6% in 2001-2002 to 16% in 2005-2006, p<0.001), while the proportion of children prescribed an ICS dose of >400 mcg decreased from 16.2% to 11.7% (P<0.001). The proportion of children prescribed an add-on therapy and an ICS dose >400 µg, increased from 38.8 % in 2001-2002 to 61.2% in 2005-2006 (p<0.001). CONCLUSIONS: Although adherence with asthma management guidelines is not optimal, this study has identified improved adherence in primary care.

Alpha-nicotinic acetylcholine receptor and tobacco smoke exposure: effects on bronchial hyperresponsiveness in children.

BACKGROUND: The CHRNA 3 and 5 genes on chromosome 15 encode the alpha subunits of the nicotinic acetylcholine receptor, mediating airway cholinergic activity. Polymorphisms are associated with cigarette smoking, chronic obstructive pulmonary disease, and lung cancer. AIMS: To determine possible associations between CHRNA 3/5 SNP rs8034191 and asthma or lung function in children in one local and one replicate multinational population, and assess if tobacco smoke modified the associations. MATERIALS AND METHODS: The rs8034191 SNP genotyped in 551 children from the environment and childhood asthma (ECA) birth cohort study in Oslo, Norway, and in 516 families from six European centers [the Genetics of Asthma International Network (GAIN) study] was tested for genotypic or allelic associations to current or history of asthma, allergic sensitization (≥ one positive skin prick tests), bronchial hyperresponsiveness (BHR), and lung function (FEV(1%) of predicted and FEV(1) /FVC ratio over/ below the 5th percentile). RESULTS: Although the TT and CT genotypes at SNP rs 8034191 were overall significantly associated with BHR (OR = 3.9, 95% CI 1.5-10.0, p = 0.005), stratified analyses according to exposure to maternal smoking in-utero or indoor smoking at 10 yrs of age showed significant association (OR = 4.4, 95% CI 1.5-12.6, p = 0.006 and OR 5.6, 95% CI 1.7-18.5, p = 0.004, respectively) only in the non-exposed and not in exposed children. The SNP-BHR association was replicated in the non-tobacco-smoke-exposed subjects in one of the GAIN centers (BHR associated with the T allele (p = 0.034)), but not in the collated GAIN populations. Asthma, allergic sensitization, and lung function were not associated with the rs8034191 alleles. CONCLUSION: An interaction between tobacco smoke exposure and a CHRNA3/5 polymorphism was found for BHR in children, but CHRNA3/5 was not associated with asthma or lung function.

First- and second-trimester fetal size and asthma outcomes at age 10 years.

RATIONALE: Greater early fetal size is associated with reduced asthma risk and improved lung function in early childhood. OBJECTIVES: To test the hypothesis that associations between early fetal size, asthma symptoms, and lung function persist into later childhood. METHODS: In a longitudinal study, first- and second-trimester fetal measurements were recorded. At 10 years of age a respiratory questionnaire was completed. Spirometry, bronchial challenge, and skin-prick testing were undertaken in a subset. MEASUREMENTS AND MAIN RESULTS: Fetal measurements were available in the first trimester for 853 individuals and the second trimester for 1,453. Questionnaires were returned for 927 children and 449 underwent detailed phenotyping. For each millimeter increase in first trimester size, asthma risk reduced by 6% (95% confidence interval[CI], 1­11) and FEV1 was higher by an average of 6 ml (95% CI, 1­11).First-trimester size was reduced in those with asthma at both 5 and 10 years compared with early or late onset wheeze (P , 0.02). Compared with persistent high growth in first and second trimesters,persistent low growth was associated with increased asthma risk(odds ratio, 2.8; 95% CI, 1.2­6.9) and a mean reduction in FEV1 of 103 ml (95% CI, 13­194), whereas increasing fetal size was associated with increased eczema risk (odds ratio, 2.5; 95% CI, 1.2­5.3). CONCLUSIONS: Reduced fetal size from the first trimester is associated with increased risk for asthma and obstructed lung function in childhood. Relative change in size after the first trimester is associated with eczema.

Paracetamol prescribing in primary care: too little and too much?

AIMS: To assess the level of paracetamol off label prescribing in the community and the potential for paracetamol under or overdosing. METHODS: The Scottish Practice Team Information (PTI) database containing prescribing data for approximately 35,839 children aged (0-12 years) was analysed for paracetamol prescriptions for the year 2006. Off label prescribing was defined as prescribing outside the BNFc age and dose recommendations. RESULTS: Two thousand seven hundred and sixty-one children aged 0-12 years were issued with 4423 prescriptions for paracetamol. (1446 males). Children 1-5 years (1329, 42.2%) accounted for 48.9% (2164) of all paracetamol prescriptions. Eighteen per cent (793) of individual prescriptions were off label and after accounting for repeat prescriptions 625 (22.75%) individuals were exposed to off label prescriptions. A further 15% (668) of prescriptions contained insufficient dosage data to determine their status, 13.3% (368) being underdosed and 4.4% (121) overdosed at least once during the study year. In total 11.3% (502) of all prescriptions were classified as underdose, 2.9% (127) as overdose and 15% (667) had no dosage instructions. Age was significantly related to non recommended dosage (χ(2) test, P < 0.001). Children 1-3 months old were at highest risk of being overdosed; 27% of prescriptions recommended actual or potential overdosage and 25% (354) of children aged 6-12 years were prescribed an actual or potential underdose. Overall 57.2% of all prescriptions failed to comply with current BNFc recommendations. CONCLUSION: Paracetamol off label prescribing is common in primary care, with relatively high levels of potential overdosing in the youngest children and potential underdosing in the oldest children.

Parental reporting of adverse drug reactions associated with attention-deficit hyperactivity disorder (ADHD) medications in children attending specialist paediatric clinics in the UK.

BACKGROUND: The development of systems to ensure appropriate and informed use of medicines in children is a global priority. Current pharmacovigilance systems, such as the UK Yellow Card Scheme, are limited by opportunistic reporting of adverse drug reactions (ADRs), lack of a denominator and lower than expected reporting rates. OBJECTIVE: To develop a pharmacovigilance system able to target specific patient populations such as children, and specific medicines of interest, using specialist medical clinics. METHODS: Between January and March 2010, parents of 578 children (3-16 years of age) receiving pharmacological therapy for attention-deficit hyperactivity disorder and attending a child and adolescent clinic in the UK were sent an ADR questionnaire to elicit information on possible ADRs associated with their child's medication use. Two approaches, free text and a symptom tick list, were used to elicit possible ADRs. RESULTS: Two hundred and seven questionnaires were returned, of which 200 were evaluable, giving a response rate of 35.9%. 123 questionnaires reported a total of 213 free-text ADRs perceived by the parents to be due to the medications under study. Two-thirds of reported ADRs were considered to be ongoing at the time of reporting. Duration of reported ADRs ranged from 1 week to 3 years. 81 returned questionnaires reported 134 different ADRs for methylphenidate monotherapy. For methylphenidate, the most frequently reported ADRs were loss of appetite (34.3%), headache (17.9%), mood and emotional problems (14.9%), stomach upset (14.9%), sleep disturbance (10.4%), and rash and other skin problems (5.2%). 467 possible drug-related symptoms were reported using the tick-list approach. Using the tick list, the most frequently reported symptoms were mood and emotional problems (28.1% [131/467]), stomach and abdominal problems (13.3% [62/467]), insomnia (12.8% [60/467]) and lack of appetite (12.6% [59/467]). The symptom tick list identified a broader range of possible adverse effects not reported as free-text ADRs, such as schooling difficulties, hearing problems, cough and blurred vision. CONCLUSIONS: The results of our study demonstrate the feasibility of using specialist clinics to target both at-risk patient populations and/or medicines of interest. We have also clearly demonstrated the practicality and feasibility of parental reporting. Parents reported common and less common ADRs, such as suicidal ideation, using both the free text and symptom tick-list approach.

Using primary care prescribing databases for pharmacovigilance.

AIMS: In the UK, adverse drug reactions (ADRs) are responsible for over 6.5% of all hospital admissions, representing a significant morbidity and cost burden to the health service. We aimed to develop an ADR monitoring system capable of identifying the reasons for patient discontinuation of drug therapy within 6 months of the index prescription. METHODS: Patients first prescribed amlodipine between 1 March 2004 and 28 February 2007 who discontinued their amlodipine medication within 6 months of the index prescription were identified from the practice team information (PTI) database. Once identified, reasons for amlodipine discontinuation were assessed by an electronic database search using relevant Readcodes and key words and by a direct approach to the primary care medical records. RESULTS: The PTI database identified 995 patients [61.4% females, mean age 65.9 years (SD 12.4 years)] who discontinued amlodipine within 6 months of an index prescription. An electronic search of the database, using Readcodes, identified that 19.4% (193) of patients who discontinued their medication had an ADR recorded in the database. Six (20%) of 30 participating primary care practices, contributing to the PTI database, agreed to be approached directly and supply the reasons for discontinuation for the 51 patients identified as having discontinued amlodipine in their practices. Completed data were returned for all 51 patients, 98% of whom discontinued amlodipine due to an ADR or adverse drug event. CONCLUSIONS: The results of this study confirm that primary care prescribing databases can be easily used to identify the frequency and nature of ADRs occurring in an ADR-enriched population identified through medication discontinuation.

Can finger-prick sampling replace venous sampling to determine the pharmacokinetic profile of oral paracetamol?

UNLABELLED: WHAT IS ALREADY KNOWN ABOUT THE SUBJECT: Finger-prick blood samples are increasingly used for the clinical and biomedical measurement of drugs and endogenous substance concentration. The use of different sampling sites can give rise to different drug concentration measurements. WHAT THIS STUDY ADDS: During the absorption phase, the paracetamol concentration in finger-prick blood samples is significantly greater than that in venous blood samples, following oral administration. Finger-prick and venous blood samples will result in equivalent pharmacokinetic parameters of oral paracetamol only after distribution equilibrium is attained. The drive to increase the availability of paediatric pharmacokinetic data with minimum blood loss has led to the development of micro-sampling techniques. However studies have suggested that pharmacokinetic data from venous or capillary blood samples may not be directly comparable. AIM: The aim of this study was to determine whether paracetamol demonstrates concentration differences between finger-prick and venous blood samples. METHODS: Paired finger-prick and venous blood samples were taken at 0, 15, 30 and 60 min following 1 g oral paracetamol, from 12 male adult subjects. Paracetamol concentration was determined using HPLC and UV detection with a LLOQ of 2200 pg on column. Intra-assay coefficient of variation for paracetamol at the LLOQ was 3%. RESULTS: At 15, 30, and 60 min post dose the median finger-prick paracetamol concentration was 349%, 72%, and 9.3% greater than the equivalent venous concentrations, respectively. Regression analysis confirmed a significant relationship between finger-prick and venous paracetamol concentrations at 15 min (r(2) = 0.81, P = 0.006), at 30 min (r(2) = 0.82, P < 0.0001) and at 60 min (r(2) = 0.87, P < 0.0001) post dose. The regression equation for venous and finger-prick blood concentrations at 15, 30 and 60 min post dose were Venous(15) = Finger(15) - 3.4, Venous(30) = Finger(30) - 3.4 and Venous(60) = 0.68 Finger(60) + 3.06, respectively. CONCLUSIONS: Paracetamol demonstrates an arteriovenous difference in concentration, and the use of finger-prick samples may give rise to results which differ from those obtained with traditional venous sampling especially during the first 1 h following drug ingestion.

Associations between fetal size, maternal {alpha}-tocopherol and childhood asthma.

BACKGROUND The origins of respiratory disease might be traced back to exposures during fetal life. The aim of the present study was to explore whether there was a relationship between fetal size and respiratory outcomes at 5 years of age in the context of fetal exposure to vitamin E. METHODS A longitudinal birth cohort study was recruited (n=1924). Antenatal ultrasound scan results were identified and the following recorded: crown-rump length (CRL) in the first trimester; femur length (FL) and biparietal diameter (BPD) in the second trimester. Maternal plasma alpha-tocopherol (vitamin E) was measured at the time of the first trimester scan. At 5 years, wheeze and asthma symptoms were reported by questionnaire, and spirometry was measured. RESULTS CRL, spirometry and questionnaire data at 5 years were available for 835, 579 and 1145 individuals, respectively. There were positive associations between CRL and forced expiratory volume in 1 s (FEV(1); 5 ml increase in FEV(1) per mm CRL, p=0.001, n=283), forced vital capacity (FVC; 6 ml increase in FVC per mm CRL, p=0.001) and forced expiratory flow between 25% and 75% of FVC (FEF(25-75); 0.008 ml/s increase in FEF(25-75) per mm CRL, p=0.023), and inverse relationships with CRL and current wheeze (OR 0.59 per CRL quartile, p=0.026, n=547) and asthma (OR 0.55 per CRL quartile p=0.011). CRL was positively associated with maternal plasma alpha-tocopherol (p=0.002). CONCLUSIONS These findings support the concept of very early fetal programming of respiratory disease. Maternal vitamin E status may be one determinant for growth of the fetus and fetal lungs during early pregnancy.