Infectious disease modelling to inform policy.

With modelling becoming increasingly important in helping to inform decisions about animal diseases, it is essential that the process be optimised to gain the maximum benefit for the decision-maker. Here, the authors set out ten steps that can improve this process for all concerned. Four steps describe initialisation to ensure that the question, answer and timescale are defined; two steps describe the modelling process and quality assurance; and four steps describe the reporting stage. The authors believe that this greater emphasis at the beginning and end of a modelling project will increase the relevance of the work and understanding of the results, and thus contribute towards better decision-making.

Compte tenu de l'importance croissante de la modélisation pour documenter les décisions sur les maladies animales, il est essentiel d'optimiser le processus afin de le rendre le plus profitable possible pour les personnes décisionnaires. Les auteurs définissent dix étapes permettant d'améliorer le processus pour tous les intervenants. Quatre étapes concernent la phase de démarrage et visent à s'assurer que les questions posées, les réponses obtenues et le calendrier sont bien définis ; les deux étapes suivantes portent sur le processus de modélisation et sur l'assurance qualité ; les quatre dernières décrivent la phase d'élaboration des rapports. Les auteurs estiment que cette attention particulière accordée aux phases de démarrage et d'achèvement d'un projet de modélisation rend l'exercice plus pertinent et améliore la compréhension des résultats, ce qui contribue à une meilleure prise de décisions.

Dada la creciente importancia que está cobrando la modelización como herramienta para ayudar a fundamentar las decisiones relativas a enfermedades animales, es esencial optimizar el proceso para que las instancias decisorias puedan aprovecharlo al máximo. Los autores exponen diez pasos que pueden mejorar el proceso para cuantos trabajan en este ámbito. En cuatro pasos se describe la inicialización, que sirve para definir debidamente la pregunta, la respuesta y la escala temporal de que se trate. En otros dos pasos se describe el proceso de modelización y de garantía de calidad, mientras que en los últimos cuatro pasos se describe la fase de producción de informes. Los autores consideran que el hecho de otorgar mayor peso a las fases iniciales y finales de un proyecto de modelización hará que el trabajo gane en pertinencia y que se entiendan mejor sus resultados, lo que a su vez contribuye a un proceso más eficaz de adopción de decisiones.

Analysing livestock network data for infectious disease control: an argument for routine data collection in emerging economies.

Livestock movements are an important mechanism of infectious disease transmission. Where these are well recorded, network analysis tools have been used to successfully identify system properties, highlight vulnerabilities to transmission, and inform targeted surveillance and control. Here we highlight the main uses of network properties in understanding livestock disease epidemiology and discuss statistical approaches to infer network characteristics from biased or fragmented datasets. We use a 'hurdle model' approach that predicts (i) the probability of movement and (ii) the number of livestock moved to generate synthetic 'complete' networks of movements between administrative wards, exploiting routinely collected government movement permit data from northern Tanzania. We demonstrate that this model captures a significant amount of the observed variation. Combining the cattle movement network with a spatial between-ward contact layer, we create a multiplex, over which we simulated the spread of 'fast' ( R0 = 3) and 'slow' ( R0 = 1.5) pathogens, and assess the effects of random versus targeted disease control interventions (vaccination and movement ban). The targeted interventions substantially outperform those randomly implemented for both fast and slow pathogens. Our findings provide motivation to encourage routine collection and centralization of movement data to construct representative networks. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.

Identifying genotype specific elevated-risk areas and associated herd risk factors for bovine tuberculosis spread in British cattle.

Bovine tuberculosis (bTB) is a chronic zoonosis with major health and economic impact on the cattle industry. Despite extensive control measures in cattle and culling trials in wildlife, the reasons behind the expansion of areas with high incidence of bTB breakdowns in Great Britain remain unexplained. By balancing the importance of cattle movements and local transmission on the observed pattern of cattle outbreaks, we identify areas at elevated risk of infection from specific Mycobacterium bovis genotypes. We show that elevated-risk areas (ERAs) were historically more extensive than previously understood, and that cattle movements alone are insufficient for ERA spread, suggesting the involvement of other factors. For all genotypes, we find that, while the absolute risk of infection is higher in ERAs compared to areas with intermittent risk, the statistically significant risk factors are remarkably similar in both, suggesting that these risk factors can be used to identify incipient ERAs before this is indicated by elevated incidence alone. Our findings identify research priorities for understanding bTB dynamics, improving surveillance and guiding management to prevent further ERA expansion.

Risk-based strategies for surveillance of tuberculosis infection in cattle for low-risk areas in England and Scotland.

Disease surveillance can be made more effective by either improving disease detection, providing cost savings, or doing both. Currently, cattle herds in low-risk areas (LRAs) for bovine tuberculosis (bTB) in England are tested once every 4 years. In Scotland, the default herd testing frequency is also 4 years, but a risk-based system exempts some herds from testing altogether. To extend this approach to other areas, a bespoke understanding of at-risk herds and how risk-based surveillance can affect bTB detection is required. Here, we use a generalized linear mixed model to inform a Bayesian probabilistic model of freedom from infection and explore risk-based surveillance strategies in LRAs and Scotland. Our analyses show that in both areas the primary herd-level risk factors for bTB infection are the size of the herd and purchasing cattle from high-risk areas of Great Britain and/or Ireland. A risk-based approach can improve the current surveillance system by both increasing detection (9% and 7% fewer latent infections), and reducing testing burden (6% and 26% fewer animal tests) in LRAs and Scotland, respectively. Testing at-risk herds more frequently can also improve the level of detection by identifying more infected cases and reducing the hidden burden of the disease, and reduce surveillance effort by exempting low-risk herds from testing.

Enhanced case management can be delivered for patients with EVD in Africa: Experience from a UK military Ebola treatment centre in Sierra Leone.

BACKGROUND: Limited data exist describing supportive care management, laboratory abnormalities and outcomes in patients with Ebola virus disease (EVD) in West Africa. We report data which constitute the first description of the provision of enhanced EVD case management protocols in a West African setting. METHODS: Demographic, clinical and laboratory data were collected by retrospective review of clinical and laboratory records of patients with confirmed EVD admitted between 5 November 2014 and 30 June 2015. RESULTS: A total of 44 EVD patients were admitted (median age 37 years (range 17-63), 32/44 healthcare workers), and excluding those evacuated, the case fatality rate was 49% (95% CI 33%-65%). No pregnant women were admitted. At admission 9/44 had stage 1 disease (fever and constitutional symptoms only), 12/44 had stage 2 disease (presence of diarrhoea and/or vomiting) and 23/44 had stage 3 disease (presence of diarrhoea and/or vomiting with organ failure), with case fatality rates of 11% (95% CI 1%-58%), 27% (95% CI 6%-61%), and 70% (95% CI 47%-87%) respectively (p = 0.009). Haemorrhage occurred in 17/41 (41%) patients. The majority (21/40) of patients had hypokalaemia with hyperkalaemia occurring in 12/40 patients. Acute kidney injury (AKI) occurred in 20/40 patients, with 14/20 (70%, 95% CI 46%-88%) dying, compared to 5/20 (25%, 95% CI 9%-49%) dying who did not have AKI (p = 0.01). Ebola virus (EBOV) PCR cycle threshold value at baseline was mean 20.3 (SD 4.3) in fatal cases and 24.8 (SD 5.5) in survivors (p = 0.007). Mean national early warning score (NEWS) at admission was 5.5 (SD 4.4) in fatal cases and 3.0 (SD 1.9) in survivors (p = 0.02). Central venous catheters were placed in 37/41 patients and intravenous fluid administered to 40/41 patients (median duration of 5 days). Faecal management systems were inserted in 21/41 patients, urinary catheters placed in 27/41 and blood component therapy administered to 20/41 patients. CONCLUSIONS: EVD is commonly associated life-threatening electrolyte imbalance and organ dysfunction. We believe that the enhanced levels of protocolized care, scale and range of medical interventions we report, offer a blueprint for the future management of EVD in resource-limited settings.

Use of genomics to track bovine tuberculosis transmission.

The control of any infectious disease of livestock is made more difficult by the presence of a wildlife reservoir, as the reservoir is often poorly observed and difficult to manage. This problem is particularly acute for bovine tuberculosis (bTB) because the long duration of infection and low levels of infectiousness make tracing the sources of infection difficult. For over 30 years, the process of contact tracing has been aided by the exploitation of molecular markers in the pathogen, but this has largely only been capable of characterising broad associations between large communities of similar types. However, the recent advent of mass high-throughput 'whole-genome' sequencing (WGS) has revolutionised forensic epidemiology for other diseases, and now it has the potential to do so for bTB. In this review, the authors consider the historical context of WGS use and look at what prior molecular techniques have already achieved. They outline the key approaches to interpreting WGS data and consider both the role of advanced analytical techniques that exploit the evolutionary and epidemiological properties of the system and the problems associated with quantifying the role of hidden reservoirs of disease. Finally, they consider the particular difficulties associated with developing this technology for routine diagnostics and its potential for mass use.

Les maladies infectieuses affectant les animaux d'élevage sont plus difficiles à contrôler lorsqu'il existe un réservoir sauvage, celui-ci étant souvent difficile à observer et à gérer. Ce problème est particulièrement crucial dans le cas de la tuberculose bovine en raison de la durée prolongée de l'infection et des faibles niveaux d'infectiosité qui rendent difficile le traçage des sources d'infection. Pendant plus de 30 ans, le processus de traçage des contacts s'est appuyé sur l'exploitation de marqueurs moléculaires au sein de l'agent pathogène, mais cette technique n'a guère pu aller au-delà d'une caractérisation d'associations générales entre vastes communautés de types similaires. L'avènement récent du séquençage massif à haut débit du génome entier a toutefois révolutionné l'épidémiologie légale appliquée à d'autres maladies, et il en ira bientôt probablement de même pour la tuberculose bovine. Les auteurs de cette synthèse s'intéressent au contexte historique de la mise au point du séquençage du génome entier en relevant ce que les techniques moléculaires antérieures avaient déjà accompli. Ils soulignent les principales méthodes pour interpréter les données générées par le séquençage du génome entier et examinent aussi bien le rôle des techniques analytiques les plus avancées basées sur l'exploitation des propriétés évolutionnistes et épidémiologiques du système que les problèmes qui se posent lorsqu'on cherche à quantifier le rôle joué par les réservoirs inapparents d'une maladie. Enfin, ils exposent les difficultés particulières liées à la mise en oeuvre de cette technologie pour des applications diagnostiques de routine ainsi que son potentiel d'utilisation à grande échelle.

La presencia de un reservorio en la fauna salvaje siempre complica la lucha contra las enfermedades infecciosas del ganado, en la medida en que esos reservorios son observados con poca frecuencia y resultan difíciles de gestionar. Este problema cobra especial gravedad en el caso de la tuberculosis bovina, pues la larga duración de la infección y los bajos niveles de infecciosidad hacen difícil localizar el origen de los focos. Durante más de 30 años se han empleado marcadores moleculares del patógeno como método auxiliar en el proceso de localización de los contactos, pero ello casi siempre ha servido únicamente para caracterizar correlaciones más bien laxas entre grandes comunidades de tipos parecidos. En los últimos tiempos, sin embargo, el advenimiento de la secuenciación masiva de alto rendimiento de genomas completos ha revolucionado la epidemiología forense aplicada a otras enfermedades, y ahora puede ocurrir otro tanto con la tuberculosis bovina. Los autores, tras repasar el contexto histórico del uso de la secuenciación de genomas completos, exponen los resultados que hasta la fecha se han podido obtener con las técnicas moleculares anteriores. Asimismo, describen brevemente los principales métodos para interpretar los datos de secuenciación de genomas completos y examinan tanto la función de las técnicas analíticas avanzadas que explotan las propiedades evolutivas y epidemiológicas del sistema como los problemas que surgen para cuantificar la intervención de reservorios ocultos de enfermedad. Por último, exponen las especiales dificultades que plantea el desarrollo de esta tecnología para efectuar diagnósticos sistemáticos y las posibilidades que ofrece para una utilización generalizada.

The healthcare workers' clinical skill set requirements for a uniformed international response to the Ebola virus disease outbreak in West Africa: the Canadian perspective.

Since December 2013, the Zaire Ebola virus disease (EVD) epidemic has ravaged West Africa. In collaboration with the Public Health Agency of Canada, healthcare workers (HCWs) and support staff from the Royal Canadian Medical Services (RCMS) of the Canadian Armed Forces (CAF) were deployed to Kerry Town, Sierra Leone. A total of 79 RCMS personnel deployed over the course of the 6-month mission in collaboration with the British Armed Forces to support efforts in West Africa. The treatment centre was mandated to treat international and local HCWs exposed to the infection. The goal of the Ebola virus disease treatment unit (EVDTU) was to provide care to affected HCWs and a beacon to attract and engage foreign HCWs to work in one of the international non-governmental organisation Ebola treatment centres in Sierra Leone. We focus on the CAF experience at the Kerry Town Ebola treatment unit in Sierra Leone in particular on the various clinical skill sets demonstrated in physicians, nurses and medical technicians deployed to the EVDTU. We outline some of the staffing challenges that arose and suggest that the necessary clinical skills needed to effectively manage patients with EVD in an austere environment can be shared across a small and diverse team of healthcare providers.

Plasmodium knowlesi transmission: integrating quantitative approaches from epidemiology and ecology to understand malaria as a zoonosis.

The public health threat posed by zoonotic Plasmodium knowlesi appears to be growing: it is increasingly reported across South East Asia, and is the leading cause of malaria in Malaysian Borneo. Plasmodium knowlesi threatens progress towards malaria elimination as aspects of its transmission, such as spillover from wildlife reservoirs and reliance on outdoor-biting vectors, may limit the effectiveness of conventional methods of malaria control. The development of new quantitative approaches that address the ecological complexity of P. knowlesi, particularly through a focus on its primary reservoir hosts, will be required to control it. Here, we review what is known about P. knowlesi transmission, identify key knowledge gaps in the context of current approaches to transmission modelling, and discuss the integration of these approaches with clinical parasitology and geostatistical analysis. We highlight the need to incorporate the influences of fine-scale spatial variation, rapid changes to the landscape, and reservoir population and transmission dynamics. The proposed integrated approach would address the unique challenges posed by malaria as a zoonosis, aid the identification of transmission hotspots, provide insight into the mechanistic links between incidence and land use change and support the design of appropriate interventions.

Impact of personal protective equipment on clinical output and perceived exertion.

BACKGROUND AND AIM: Safe clinical care within Ebola Virus Disease Treatment Units (EVDTUs) mandate the use of personal protective equipment (PPE), comprising a fluid impermeable hooded suit, visor, gloves and rubber boots. The aim of this study was to assess the impact of this PPE on clinical personnel's performance in the EVDTU, Kerry Town, Sierra Leone. METHODS: An anonymous questionnaire was administered to healthcare professionals (HCPs) entering the EVDTU ward area (Red Zone (RZ)), during a 2-week period to assess perceived exertion using the Borg Rating of Perceived Exertion Scale. RESULTS: A total of 62 clinical episodes undertaken by 20 HCPs were analysed. There were no episodes of heat illness during the study. HCPs spent a median of 74 (IQR 55-95) minutes within the RZ. Median durations of RZ activity were similar throughout the 24 h period (p=0.22), but Borg scores were significantly higher between 11:00 and 14:59 compared with RZ entry between 15:00 and 10:59, respectively (12 (6-15), n=13; 8 (6-9), n=48; p=0.022). Rates of weight loss per minute spent within the RZ were significantly greater between 11:00 and 14:59 compared with 15:00-10:59, respectively (0.014 (0.009-0.023) kg/min, n=6; 0.007 (0.004-0.013) kg/min, n=37; p=0.037). CONCLUSIONS: Despite acclimatisation and proactive clinical tasking, HCPs in the EVDTU experienced significantly greater rates of weight loss and perceived exertion scores during the hottest times of the day. These findings should be considered by those planning healthcare facilities for future humanitarian missions where HCPs will provide clinical care in full PPE.

Estimating epidemiological parameters for bovine tuberculosis in British cattle using a Bayesian partial-likelihood approach.

Fitting models with Bayesian likelihood-based parameter inference is becoming increasingly important in infectious disease epidemiology. Detailed datasets present the opportunity to identify subsets of these data that capture important characteristics of the underlying epidemiology. One such dataset describes the epidemic of bovine tuberculosis (bTB) in British cattle, which is also an important exemplar of a disease with a wildlife reservoir (the Eurasian badger). Here, we evaluate a set of nested dynamic models of bTB transmission, including individual- and herd-level transmission heterogeneity and assuming minimal prior knowledge of the transmission and diagnostic test parameters. We performed a likelihood-based bootstrapping operation on the model to infer parameters based only on the recorded numbers of cattle testing positive for bTB at the start of each herd outbreak considering high- and low-risk areas separately. Models without herd heterogeneity are preferred in both areas though there is some evidence for super-spreading cattle. Similar to previous studies, we found low test sensitivities and high within-herd basic reproduction numbers (R0), suggesting that there may be many unobserved infections in cattle, even though the current testing regime is sufficient to control within-herd epidemics in most cases. Compared with other, more data-heavy approaches, the summary data used in our approach are easily collected, making our approach attractive for other systems.

A metapopulation model for highly pathogenic avian influenza: implications for compartmentalization as a control measure.

Although the compartmentalization of poultry industry components has substantial economic implications, and is therefore a concept with huge significance to poultry industries worldwide, the current requirements for compartment status are generic to all OIE member countries. We examined the consequences for potential outbreaks of highly pathogenic avian influenza in the British poultry industry using a metapopulation modelling framework. This framework was used to assess the effectiveness of compartmentalization relative to zoning control, utilizing empirical data to inform the structure of potential epidemiological contacts within the British poultry industry via network links and spatial proximity. Conditions were identified where, despite the efficient isolation of poultry compartments through the removal of network-mediated links, spatially mediated airborne spread enabled spillover of infection with nearby premises making compartmentalization a more 'risky' option than zoning control. However, when zoning control did not effectively inhibit long-distance network links, compartmentalization became a relatively more effective control measure than zoning. With better knowledge of likely distance ranges for airborne spread, our approach could help define an appropriate minimum inter-farm distance to provide more specific guidelines for compartmentalization in Great Britain.

Discovery of HLA-DRB1*03:20 allele in a Taiwanese volunteer hematopoietic stem cell donor and the probable HLA-A, -B, -C and -DRB1 haplotype in association with DRB1*03:20.

The allele HLA-DRB1*03:20, a variant of DRB1*03, was first reported to the IMGT HLA database in April 2001 without indication on the ethnicity of the blood donor (Cell ID: HC 125775). We found a Taiwanese volunteer hematopoietic stem cell donor carries DRB1*03:20 by a sequence-based typing (SBT) method. The DNA sequence of DRB1*03:20 is identical to the sequence of DRB1*03:01:01 in exon 2, except a nucleotide substitution at position 341(T→C) (GTT→GCT at codon 85). The nucleotide replacement produced an amino acid variation at residue 85 (V→A). We hypothesize that DRB1*03:20 was probably derived from DRB1*03:01:01 via a nucleotide point mutation event. The probable HLA haplotype in association with DRB1*03:20 was deduced as A*11:02-B*58:01-C*07:02-DRB1*03:20. We here report the Taiwanese/Chinese ethnicity of DRB1*03:20.

Developing a framework for risk-based surveillance of tuberculosis in cattle: a case study of its application in Scotland.

Due to its substantially lower prevalence of bovine tuberculosis (bTB) relative to other areas of Great Britain, Scotland was designated as an officially (bovine) TB-free region in 2009. This paper investigates resultant possibilities for reducing surveillance by developing risk-based alternatives to current 4-year testing of eligible herds. A model of freedom of infection was used to develop strategies that specifically tested herds that are at risk of infection but would probably not be identified by slaughterhouse meat inspection. The performance of current testing is mimicked by testing all herds that slaughter fewer than 25% of their total stock per year and regularly import animals from high-incidence areas of England and Wales or from Ireland. This system offers a cost reduction by requiring 25% fewer herd and animal tests and 25% fewer false positives.

Recognition of a Caucasoid HLA-B locus allele, B*44:55, in a Taiwanese/Chinese bone marrow stem cell donor.

We detected a Caucasoid HLA-B allele, HLA-B*44:55, in a potential Taiwanese/Chinese bone marrow hematopoietic stem cell donor during our routine HLA SBT (sequence-based typing) practice. The sequence of B*44:55 varies with B*44:02:01:01 with one nucleotide in exon 2 at position 97 (T->C), while it differs from B*44:03:01 with one nucleotide in exon 2 at position 97 (T->C) and three nucleotides in exon 3 at residues 538-540 (CTG->GAC). The nucleotide replacements caused one amino acid variation with B*44:02:01:01 at residue 9 (Y->H) and two amino acid variations with B*44:03:01 at residue 9 (Y->H) and residue 156 (L->D). The formation of B*44:55 is probably the result of a nucleotide substitution involving B*44:02:01:01 at position 97 (T->C). The Taiwanese/Chinese donor with B*44:55 claims having no kinship with Caucasian. Our speculations on the origin of the Taiwanese/Chinese B*44:55 will be presented.

Discovery of the novel HLA-DRB1*09:01:08 allele in a Taiwanese volunteer bone marrow donor and identification of the probable HLA-A, HLA-B and HLA-DRB1 haplotype in association with DRB1*09:01:08.

We report here the novel variant of HLA-DRB1*09:01, DRB1*09:01:08, discovered in a Taiwanese volunteer bone marrow donor by a sequence-based typing (SBT) method. The DNA sequence of DRB1*09:01:08 is identical to the sequence of DRB1*09:01:02 in exon 2 except a silent mutation at nucleotide position 261(C→T) (GCC→GCT at codon 58). We hypothesize DRB1*09:01:08 was probably derived from DRB1*09:01:02 via a nucleotide point mutation event. The plausible HLA-A, HLA-B and HLA-DRB1 haplotype in association with DRB1*09:01:08 was deduced as A*02:07-B*46:01-DRB1*09:01:08.

A novel HLA-B allele, B*58:01:12, detected in a Taiwanese volunteer bone marrow stem cell donor using sequence-based typing method.

Human leukocyte antigen-B*58:01:12, a novel rare allele of HLA-B*58:01 variant, was found in a Taiwanese volunteer bone marrow donor by SBT (sequence-based typing) method. The DNA sequence of B*58:01:12 is identical to the sequence of B*58:01:01 in exons 2, 3 and 4 except at nucleotide position 483 where nucleotide C is substituted by T (at codon 137; GAC GAT). Due to the silent point mutation, the amino acid sequence of B*58:01:12 is identical to the sequence of B*58:01:01. The HLA haplotype in association with B*58:01:12 may be deduced as A*33:03-B*58:01:12-DRB1*03:01. The discovery of B*58:01:12 adds further polymorphism of B*58:01 in Taiwanese population.

Discovery of the novel HLA-DRB1*04:05:14 allele in a Taiwanese unrelated haematopoietic stem cell donor by a sequence-based typing method.

We report here a de novo HLA-DRB1*04 allele, DRB1*04:05:14, discovered in a Taiwanese unrelated volunteer bone marrow stem cell donor by a sequence-based typing method. In exon 2, the DNA sequence of DRB1*04:05:14 is identical to the sequence of DRB1*04:05:01 except the nucleotide at positions 321 where C is replaced by T (at codon 78; TAC→TAT). Due to the silent mutation, the nucleotide substitution produced no amino acid variation in comparison with DRB1*04:05:01. We assume DRB1*04:05:14 was derived from DRB1*04:05:01 via a point mutation. The probable HLA-A, -B and -DRB1 haplotype in association with DRB1*04:05:14 may be deduced as A*11-B*55-DRB1*04:05:14. We here report the Taiwanese ethnicity of DRB1*04:05:14.

Discovery of the novel HLA-DRB1*10:04 allele in a Taiwanese volunteer bone marrow donor and identification of the probable HLA-A, -B, -C and -DRB1 haplotype in association with DRB1*10:04.

We report here a novel variant of HLA-DRB1*10, DRB1*10:04, discovered in a Taiwanese volunteer bone marrow donor by a sequence-based typing (SBT) method. The DNA sequence of DRB1*10:04 differs from DRB1*10:01:01, in exon 2, at nucleotide positions 296 (G fi A) and 303 (T fi G). The nucleotide changes caused an amino acid substitution at amino acid residue 70 (R fi Q). We hypothesize that the formation of DRB1*10:04 was probably the result of a gene recombination event where DRB1*10:01:01 received a minimum length of DNA sequence from DRB1*04:05:01, as the sequence of DRB1*10:04 is identical to DRB1*10:01:01 in exon 2 except the sequence from nucleotide 296 to nucleotide 303, which is identical to DRB1*04:05:01. The plausible HLA-A, -B, -C and - DRB1 haplotypes in association with DRB1*10:04 was deduced as A*01:01-B*37:01-C*06:02-DRB1*10:04.

Does concomitant use of paracetamol potentiate the gastroduodenal mucosal injury associated with aspirin? A prospective, randomised, pilot study.

BACKGROUND: Paracetamol is commonly prescribed for first-line symptomatic treatment in patients with osteoarthritis and aspirin is often co-administered for cardiovascular prophylaxis. It is not known if an interaction exists between aspirin and paracetamol in regards to gastroduodenal mucosal injury. AIM: To investigate whether or not co-administered aspirin with paracetamol results in an increased rate of endoscopic gastroduodenal mucosal injury as compared to either agent alone. METHODS: In this prospective, double-blind, randomised, three-arm, placebo- and active-controlled, parallel-group pilot study healthy adult subjects (18-75 years old) with a normal baseline trans-nasal oesophagogastroduodenoscopy (TN-EGD), received oral paracetamol 4000 mg q.d.s. (n = 21), aspirin 325 mg q.d.s. (n = 19) or paracetamol 4000 mg q.d.s. and aspirin 325 mg q.d.s. (n = 20). Upper gastrointestinal mucosal injury was evaluated after 7 days of treatment with TN-EGD. RESULTS: The rate of gastric ulcers in subjects receiving paracetamol (0/21, 0%) alone or aspirin (3/19, 16%) or both (2/20, 10%) was not different. There were, however, significantly more subjects with one or more lesions (erosion or ulcer) per subject in the paracetamol and aspirin (16/20, 80%) treated subjects as compared to the aspirin (8/19, 42%, P < 0.001) or the paracetamol (3/21, 14%, P < 0.01) exposed subjects. The mean number of lesions per subject was also greater (7.9 vs. 0.7, P < 0.01) in those treated with aspirin and paracetamol compared to paracetamol alone. CONCLUSIONS: Co-administration of paracetamol and aspirin was not associated with a significant difference in endoscopic ulcer rates compared to either drug alone. There was a strong signal for increased endoscopic erosions and ulcers in the combined group compared to either aspirin or paracetamol alone.