Harnessing the potential of data-driven strategies to optimise transfusion practice.

No one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.

Where does the Albumin go? Human Albumin Solution usage following the implementation of a demand management programme.

OBJECTIVE: To outline the Guy's and St Thomas' NHS Foundation Trust (GSTFT) and Evelina London Children's Hospital (ELCH) demand management plan for human albumin solution (HAS) and usage. BACKGROUND: There is no UK-wide guidance governing the use of HAS. A severe shortage in 2015 prompted a Trust demand management programme. Indications were categorised according to locally agreed colour code and ASFA categories. METHODS: Following the implementation of the demand management programme, a 6-month audit of HAS usage was completed. RESULTS: A total of 1303.1 L of HAS was used in 1139 infusions; 737 infusions were 20% HAS, accounting for 175.7 L (13.5%) in 181 patients. Indications for 20% HAS were red in 53.9% (94.7 L), blue in 26.5% (46.5 L) and grey in 19.6% (34.5 L). The remaining 1127.4 L (86.5%) infused were of 4.5 and 5 % HAS. A total of 1102.3 L (97.8%) was used for plasma exchange, 941.4 L (85.4%) ASFA category I, 93.7 L (8.5%) category II, 25.5 L (2.3%) category IV and 41.7 L (3.8%) for indications not specified according to ASFA; 25.1 L (2.2%) were used for a grey indication (volume resuscitation for hypovolaemia). CONCLUSIONS: The demand management programme provides surveillance of indications and retrospective verification of appropriate use. The majority of HAS indications were appropriate. Plasma exchange accounted for 84.6% of HAS usage and will be the focus of further demand management strategies. The demand management programme whilst aiming to promote best transfusion practice also ensures a tool to manage future shortages according to indication and available supply.

How I treat heterozygous hereditary antithrombin deficiency in pregnancy.

Untreated hereditary antithrombin deficiency in pregnancy is associated with maternal venous thromboembolism (VTE) and possibly with fetal loss. Thromboprophylaxis during pregnancy is recommended, but dosages remain controversial.Our objective was to perform a retrospective assessment of thrombotic events and pregnancy outcomes in women with hereditary antithrombin deficiency managed according to a standard protocol. Pregnancies in individuals with hereditary antithrombin deficiency were identified from a hospital database. Women with no prior VTE received enoxaparin 40 mg daily until 16 weeks gestation and thereafter 40 mg twice daily. Women with prior VTE received intermediate dose enoxaparin (1 mg/kg) once daily, increased to twice daily at 16 weeks and anti-Xa monitored dosing. Thromboprophylaxis was stopped at initiation of labour or 12 hours prior to caesarean and 50 IU/kg antithrombin concentrate given. Thromboprophylaxis was restarted after delivery. Eighteen pregnancies in 11 women with antithrombin deficiency were identified. Seventeen pregnancies (94%) were successful. Median gestation was 39 weeks (range 30-41) and median birth-weight was 2,995 g (910-4,120 g), but 6/17 infants (35%) were small for gestational age (p=0.01). Estimated blood loss at delivery was median 375 ml (200-600 ml). Four pregnancies were complicated by VTE; one newly presented with a thrombotic event, two patients were not taking thromboprophylaxis and one occurred despite thromboprophylaxis. Two novel mutations (p.Leu317Ser and p.His33GInfsX32) are described. In conclusion, in antithrombin deficiency the use of low-molecular-weight heparin in pregnancy and puerperium with antithrombin concentrate pre-delivery was associated with successful pregnancy outcome; rates of VTE appear to be lower than previously reported, but remain elevated.

Extracting cortical current dipoles from MEG recordings.

A novel way of using synthetic aperture magnetometry to extract local current dipoles is proposed. This method is used to extract the current-dipoles at multiple points in the cortex. It is shown that in this way the correlation between cortical points is lower and falls faster with distance when compared to the original MEG and other methods. Evoked auditory responses are well localized. They show higher signal to noise ratio and are more reproducible then the MEG evoked fields.

Responses of farmers to introduction in England and Wales of pre-movement testing for bovine tuberculosis.

Pre-movement testing (PrMT) for bovine tuberculosis (bTB) was introduced in England and Wales in 2 phases starting in 2006. This study used questionnaires (n=800, response rate=31%) and analysis of national cattle movement records between January 2003 and February 2007 to investigate the impact of PrMT on specific farm management behaviours. A majority of farmers (65%) believed they had not changed their behaviour in response to PrMT; the main reported changes related to decisions regarding selling of cattle. There was evidence in the cattle movement data that introduction of PrMT resulted in reduction of movements of cattle between farms in those areas which must undertake PrMT. The buying behaviour reported by farmers reflected the tendency to buy locally but some farmers reported that others might be more willing to purchase animals from high-risk areas as a result of increased confidence due to PrMT. However, there was little evidence in the movement data of increased movements from high- to low-risk bTB areas following introduction of PrMT. Analysis of the cattle movement data found increased movement of single animals and decreased movement of large batches (>10) of animals (directly) between farms since the introduction of PrMT.

Quantifying within- and between-animal variation and uncertainty associated with counts of Escherichia coli O157 occurring in naturally infected cattle faeces.

Cattle faeces are considered the most important reservoir for human infection with Escherichia coli O157. We have previously described shedding of E. coli O157 in the faeces of naturally infected cattle cohorts. However, the data require further investigation to quantify the uncertainty and variability in the estimates previously presented. This paper proposes a method for analysing both the presence and the quantity of E. coli O157 in cattle faecal samples, using two isolation procedures, one of which enumerates E. coli O157. The combination of these two measurements, which are fundamentally different in nature and yet measuring a common outcome, has necessitated the development of a novel statistical model for ascertaining the contribution of the various components of variation (both natural and observation induced) and for judging the influence of explanatory variables. Most of the variation within the sampling hierarchy was attributable to multiple samples from the same animal. The contribution of laboratory-level variation was found to be low. After adjusting for fixed and random effects, short periods of increased intensity of shedding were identified in individual animals. We conclude that within-animal variation is greater than between animals over time, and studies aiming to elucidate the dynamics of shedding should focus resources, sampling more within than between animals. These findings have implications for the identification of persistent high shedders and for assessing their role in the epidemiology of E. coli O157 in cattle populations. The development of this non-standard statistical model may have many applications to other microbial count data.

Bootstrap significance of low SNR evoked response.

In order to obtain adequate signal to noise ratio (SNR), stimulus-evoked brain signals are averaged over a large number of trials. However, in certain applications, e.g. fetal magnetoencephalography (MEG), this approach fails due to underlying conditions (inherently small signals, non-stationary/poorly characterized signals, or limited number of trials). The resulting low SNR makes it difficult to reliably identify a response by visual examination of the averaged time course, even after pre-processing to attenuate interference. The purpose of this work was to devise an intuitive statistical significance test for low SNR situations, based on non-parametric bootstrap resampling. We compared a two-parameter measure of p-value and statistical power with a bootstrap equal means test and a traditional rank test using fetal MEG data collected with a light flash stimulus. We found that the two-parameter measure generally agreed with established measures, while p-value alone was overly optimistic. In an extension of our approach, we compared methods to estimate the background noise. A method based on surrogate averages resulted in the most robust estimate. In summary we have developed a flexible and intuitively satisfying bootstrap-based significance measure incorporating appropriate noise estimation.

Validation of the flash-evoked response from fetal MEG.

Flash-evoked responses can be recorded from the fetus in utero. However, a standard analysis approach based on orthogonal projection (OP) to attenuate maternal and fetal cardiac signals leads to a spatial redistribution of the signal. This effect prevents the correlation of source location with a known fetal head location in some cases and the signal-to-noise ratio (SNR) is sometimes limited such that the response latency is difficult to determine. We used a modified beamformer model search analysis to avoid the redistribution shortcoming and to improve the SNR. We included a statistical test for residual interference in the average and quantified significance of the evoked response with a bootstrap method. Selected source locations compared favorably to fetal head locations estimated from ultrasound exams. The evoked response time course was found to have a significant post-trigger peak with a latency between about 180 and 770 ms in more than 90% of the subject measurements. These results confirm that the combined application of a beamformer model search and bootstrap significance test provides a validation of the flash-evoked response observed in OP processed fetal MEG channels.

Exploring the role of auction markets in cattle movements within Great Britain.

Within Great Britain cattle are often traded at regional markets, of which there are approximately 200 located throughout England, Scotland and Wales. The movement of animals through markets was important in the spread of foot-and-mouth disease (FMD) virus during the 2001 GB outbreak. Here, we describe the movements of cattle to and from markets for 2002-2004 and, using social network analysis, we construct networks based on these movements. In 2002, 56,227 animal holdings (AH) sent cattle to 222 cattle auction markets, compared to 58,476 AH and 187 auction markets in 2004. Auction markets vary considerably in their trading with AH. The majority of markets received animals from less than 50 AH, but one received animals from as many as 6155 AH during a year. The distances travelled between origin AH and destination AH when cattle move "directly" were found to be significantly shorter compared to distances between origin and destination AH where the movement occurred via a market. However, the vast majority of distances moved, for both types of movements, were less than 50 km. Some auction markets appear as highly connected premises within the contact network and are associated with high betweenness scores. However AH also occupy positions central to the contact network. The variation in the characteristics and role of individual markets within the contact network suggests important differences in risk of disease transmission associated with each market. Inclusion of network parameters, when considering the risk associated with moving cattle through auction markets may enhance the development of effective targeted disease control strategies.

Nicotine dependence and reward differ between adolescent and adult male mice.

The present study defined age differences in several aspects of nicotine dependence using male mice of two age groups [postnatal day (PND) 28 and PND 70]. Adolescent and adult mice displayed differences in acute sensitivity to nicotine, rewarding and withdrawal effects, development of tolerance to nicotine, and nicotinic receptor function. In the condition place preference model, adolescent mice displayed a higher sensitivity to nicotine than adults. In addition, in spontaneous and mecamylamine-precipitated withdrawal models, adolescent mice displayed fewer withdrawal signs than adults. In response to acute nicotine, it was found that adolescent mice displayed greater nicotine-induced antinociception compared with adult counterparts in the tail-flick test. Furthermore, differences in tolerance to nicotine were also noted in that adolescents developed a significantly higher degree of tolerance to nicotine in the hot-plate test compared with adults. Finally, using rubidium efflux assays, it was found that adolescent nicotinic receptors in different brain areas displayed significantly increased functionality compared with adult receptors. These data indicate that the underlying receptor mechanisms of nicotine dependence differ for adults and adolescents, suggesting that the effectiveness of smoking cessation therapies will differ for various age groups.

Recent network evolution increases the potential for large epidemics in the British cattle population.

Following the foot and mouth disease epidemic in Great Britain (GB) in 2001, livestock movement bans were replaced with mandatory periods of standstill for livestock moving between premises. It was anticipated that these movement restrictions would limit each individual's contact networks, the extent of livestock movements and thus the spread of future disease outbreaks. However, the effect of behaviour changes on the global network in adapting to these restrictions is currently unknown. Here, we take a novel approach using GB cattle movement data to construct week-by-week contact networks between animal holdings (AH) to explore the evolution of the network since this policy was introduced, the first time network theory has been used for this purpose. We show that the number of AH moving cattle as part of the giant strong component (GSC), representing the region of maximal connectivity, has been increasing linearly over time. This is of epidemiological significance as the size of the GSC indicates the number of holdings potentially exposed to disease, thus giving a lower bound of maximum epidemic size. Therefore, despite restriction of cattle movements, emergent behaviour in this self-organizing system has potentially increased the size of infectious disease epidemics within the cattle industry.

Searching for the best model: ambiguity of inverse solutions and application to fetal magnetoencephalography.

Fetal brain signals produce weak magnetic fields at the maternal abdominal surface. In the presence of much stronger interference these weak fetal fields are often nearly indistinguishable from noise. Our initial objective was to validate these weak fetal brain fields by demonstrating that they agree with the electromagnetic model of the fetal brain. The fetal brain model is often not known and we have attempted to fit the data to not only the brain source position, orientation and magnitude, but also to the brain model position. Simulation tests of this extended model search on fetal MEG recordings using dipole fit and beamformers revealed a region of ambiguity. The region of ambiguity consists of a family of models which are not distinguishable in the presence of noise, and which exhibit large and comparable SNR when beamformers are used. Unlike the uncertainty of a dipole fit with known model plus noise, this extended ambiguity region yields nearly identical forward solutions, and is only weakly dependent on noise. The ambiguity region is located in a plane defined by the source position, orientation, and the true model centre, and will have a diameter approximately 0.67 of the modelled fetal head diameter. Existence of the ambiguity region allows us to only state that the fetal brain fields do not contradict the electromagnetic model; we can associate them with a family of models belonging to the ambiguity region, but not with any specific model. In addition to providing a level of confidence in the fetal brain signals, the ambiguity region knowledge in combination with beamformers allows detection of undistorted temporal waveforms with improved signal-to-noise ratio, even though the source position cannot be uniquely determined.

Optimal reduction of MCG in fetal MEG recordings.

Recording fetal magnetoencephalographic (fMEG) signals in-utero is a demanding task due to biological interference, especially maternal and fetal magnetocardiographic (MCG) signals. A method based on orthogonal projection of MCG signal space vectors (OP) was evaluated and compared with independent component analysis (ICA). The evaluation was based on MCG amplitude reduction and signal-to-noise ratio of fetal brain signals using exemplary datasets recorded during ongoing studies related to auditory evoked fields. The results indicate that the OP method is the preferable approach for attenuation of MCG and for preserving the fetal brain signals in fMEG recordings.

Right parietal activation during delusional state in episodic interictal psychosis of epilepsy: a report of two cases.

Magnetoencephalography (MEG) was used to image brain activity associated with delusions in episodic interictal psychosis of epilepsy. Two female patients aged 65 and 68 with temporal lobe epilepsy were studied during and after a delusional state. Topographic images of the excess kurtosis (g2), the statistical index of spikelike activity, were obtained from unaveraged MEG recordings using an analysis called "synthetic aperture magnetometry" (SAM). For both patients, MEG waveforms and excess kurtosis images revealed spiky activity in the right inferior parietal region during the delusional state. A second MEG measurement after delusions were resolved with antipsychotic therapy revealed no excess kurtosis in the right parietal area. Likewise, the sharp waves on MEG recordings disappeared as well. Our results suggest association of the right inferior parietal cortex, including the supramarginal gyrus, with the delusional state of episodic interictal psychosis of epilepsy.

Automated localization of magnetoencephalographic interictal spikes by adaptive spatial filtering.

OBJECTIVE: Automated adaptive spatial filtering techniques can be applied to magnetoencephalographic (MEG) data collected from people with epilepsy. Source waveforms estimated by these methods have higher signal-to-noise ratio (SNR) than spontaneous MEG data, allowing identification and location of interictal spikes. The software tool SAM(g(2)) provides an adaptive spatial filtering algorithm for MEG data that yields source images of excess kurtosis and provides source time-courses in voxels exhibiting high excess kurtosis. The sensitivity and specificity of SAM(g(2)) in epilepsy is unknown. METHODS: Interictal MEG data from 36 patients with intractable epilepsy were analyzed using SAM(g(2)), and results compared with equivalent current dipole (ECD) fit procedures. RESULTS: When SNR of interictal spikes was high (compared to background) with a clear single focus, in most cases there was good agreement between ECD and SAM(g(2)). With multiple foci, there was typically overlap but imperfect concordance between results of ECD and SAM(g(2)). CONCLUSIONS: SAM(g(2)) may in some cases be equivalent to manual ECD fit for localizing interictal spikes with single locus and good SNR. Further studies are required to validate SAM(g(2)) with multiple foci or poor SNR. SIGNIFICANCE: In some cases, SAM(g(2)) might eventually assist or replace manual ECD analysis of MEG data.

Quantifying uncertainty associated with microbial count data: a Bayesian approach.

We consider the problem of estimating bacterial concentration in a substance, given microbial count data. A Bayesian approach is proposed which naturally allows the incorporation of both plate-count data and extra information from confirmatory tests such as genotyping by polymerase chain reaction (PCR). The estimation methods yield posterior credible regions for bacterial concentration, in contrast to the previous methods, which generally only produce point estimates. The approach is illustrated with specific reference to the enumeration of the food-borne pathogen Escherichia coli O157 by spiral plating, although the methodology can be applied to any bacterium or counting method of interest. The results obtained provide guidance to the experimenter as to the number of confirmatory tests which should be performed, and also suggest that in the initial plate count one should err on the side of including rather than excluding colonies whose genotype seems unclear.

Intermittent and persistent shedding of Escherichia coli O157 in cohorts of naturally infected calves.

AIMS: We conducted two short-term studies of cohorts of naturally infected calves to determine the prevalence and concentrations of Escherichia coli O157 shed in faeces. METHODS AND RESULTS: Two cohorts of calves were sampled; in the first study 14 calves were sampled up to five times a day for 5 days; in the second study a group of 16 separate calves were sampled once or twice a day for 15 days. All cattle within the two cohorts shed E. coli O157 at some point during the respective studies. In 18% of samples, E. coli O157 could only be isolated using immunomagnetic separation after an enrichment period, suggesting concentrations <250 CFU g(-1). The highest concentrations recorded were 6.7 x 10(5) and 1.6 x 10(6) CFU g(-1) for studies 1 and 2 respectively. CONCLUSIONS: Persistent, high shedders (shedding >10(3) CFU g(-1)) were evident in both studies but, in the majority of calves, the pathogen was isolated intermittently. SIGNIFICANCE AND IMPACT OF THE STUDY: The variable patterns of shedding have important implications for the design of appropriate sampling protocols and for gaining meaningful estimates of parameters used in mathematical models of transmission.

Development and application of a spiral plating method for the enumeration of Escherichia coli O157 in bovine faeces.

AIM: To develop and validate a direct plating method applicable to epidemiological studies for enumerating Escherichia coli O157 in cattle faeces. METHODS AND RESULTS: The spiral plate count method was used to enumerate E. coli O157 in faecal samples. The accuracy and variation of counts was then assessed using faecal samples inoculated with E. coli O157. There was good agreement between inoculated levels of E. coli O157 and those recovered from faeces, particularly when counts were > 10(2) CFU g(-1) of faeces. The method was applied to a small study assessing short-term survival of E. coli O157 in naturally infected cattle faeces. E. coli O157 was found to survive in faeces for over 10 days at concentrations above 10(3) CFU g(-1) of faeces. Populations of E. coli O157 were also found to increase 100-fold in the first few hours after defecation. CONCLUSIONS: The enumeration method is easy to implement and enables a quick throughput of large numbers of samples. The method is accurate and reliable and enables the inherent variation in count data to be explored but needs to be used in combination with a more sensitive method for samples containing < 10(2) CFU g(-1) of faeces. SIGNIFICANCE AND IMPACT OF THE STUDY: The method described is appropriate for enumeration of E. coli O157 in cattle faeces in large-scale epidemiological studies.

Human fetal brain imaging by magnetoencephalography: verification of fetal brain signals by comparison with fetal brain models.

Fetal magnetoencephalogram (fMEG) is measured in the presence of a large interference from maternal and fetal magnetocardiograms (mMCG and fMCG). This cardiac interference can be successfully removed by orthogonal projection of the corresponding spatial vectors. However, orthogonal projection redistributes the fMEG signal among channels. Such redistribution can be readily accounted for in the forward solution, and the signal topography can also be corrected. To assure that the correction has been done properly, and also to verify that the measured signal originates from within the fetal head, we have modeled the observed fMEG by two extreme models where the fetal head is assumed to be either electrically transparent or isolated from the abdominal tissue. Based on the measured spontaneous, sharp wave, and flash-evoked fMEG signals, we have concluded that the model of the electrically isolated fetal head is more appropriate for fMEG analysis. We show with the help of this model that the redistribution due to projection was properly corrected, and also, that the measured fMEG is consistent with the known position of the fetal head. The modeling provides additional confidence that the measured signals indeed originate from within the fetal head.