Economics of Robust Surveillance on Exotic Animal Diseases: the Case of Bluetongue

Control of emerging animal diseases critically depends on their early detection. However, designing surveillance programs for exotic and emerging diseases is very challenging because of knowledge gaps on the probability of incursion and mechanisms of spread. Using the example of Bluetongue Virus, which is exotic to the UK, we develop a metapopulation epidemic-economic modelling framework that considers the incursion, detection, spread and control of a disease in a livestock production system composed of heterogeneous subpopulations. The model is then embedded in an information gap (info-gap) framework to assess the robustness of surveillance and vaccination policies to unacceptable outbreaks losses and applied to the case of Bluetongue in the UK. The results show that active reporting of suspect clinical signs by farmers is a very robust way to reduce unacceptable outcomes. Vaccination of animals in high risk regions led to robustly protective programs. If vaccines are not available, surveillance targeted to the high risk region is very robust even if the extent of the high risk region is not known and effectiveness of detection is very low. Surveillance programs focusing in all regions with the same intensity are in general not robust unless the dispersal of the vector connecting both regions is very high.compartmental epidemic model, emergent animal disease, Knightian uncertainty, sentinel surveillance system, Livestock Production/Industries,

Complete genome sequence of Parvibaculum lavamentivorans type strain (DS-1T)

Parvibaculum lavamentivorans DS-1T is the type species of the novel genus Parvibaculum in the novel family Rhodobiaceae (formerly Phyllobacteriaceae) of the order Rhizobiales of Alphaproteobacteria. Strain DS-1T is a non-pigmented, aerobic, heterotrophic bacterium and represents the first tier member of environmentally important bacterial communities that catalyze the complete degradation of synthetic laundry surfactants. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 3,914,745 bp long genome with its predicted 3,654 protein coding genes is the first completed genome sequence of the genus Parvibaculum, and the first genome sequence of a representative of the family Rhodobiaceae

Evaluation of the methodological quality of studies of the performance of diagnostic tests for bovine tuberculosis using QUADAS

There has been little assessment of the methodological quality of studies measuring the performance (sensitivity and/or specificity) of diagnostic tests for animal diseases. In a systematic review, 190 studies of tests for bovine tuberculosis (bTB) in cattle (published 1934-2009) were assessed by at least one of 18 reviewers using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist adapted for animal disease tests. VETQUADAS (VQ) included items measuring clarity in reporting (n = 3), internal validity (n = 9) and external validity (n = 2). A similar pattern for compliance was observed in studies of different diagnostic test types. Compliance significantly improved with year of publication for all items measuring clarity in reporting and external validity but only improved in four of the nine items measuring internal validity (p < 0.05). 107 references, of which 83 had performance data eligible for inclusion in a meta-analysis were reviewed by two reviewers. In these references, agreement between reviewers' responses was 71% for compliance, 32% for unsure and 29% for non-compliance. Mean compliance with reporting items was 2, 5.2 for internal validity and 1.5 for external validity. The index test result was described in sufficient detail in 80.1% of studies and was interpreted without knowledge of the reference standard test result in only 33.1%. Loss to follow-up was adequately explained in only 31.1% of studies. The prevalence of deficiencies observed may be due to inadequate reporting but may also reflect lack of attention to methodological issues that could bias the results of diagnostic test performance estimates. QUADAS was a useful tool for assessing and comparing the quality of studies measuring the performance of diagnostic tests but might be improved further by including explicit assessment of population sampling strategy.The SE3238 project “Meta-analysis of diagnostic tests and modelling to identify appropriate testing strategies to reduce M. bovis infection in GB herds” was funded by the UK Department for Environment, Food and Rural Affairs (Defra).http://www.elsevier.com/locate/prevetmedam2018Veterinary Tropical Disease

Meta-analyses of the sensitivity and specificity of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis in the UK and Ireland

Publication history: Accepted - 26 February 2017; Published online - 6th March 2017.Bovine Tuberculosis (bTB) in cattle is a global health problem and eradication of the disease requires accu-rate estimates of diagnostic test performance to optimize their efficiency. The objective of this study was,through statistical meta-analyses, to obtain estimates of sensitivity (Se) and specificity (Sp), for 14 differ-ent ante-mortem and post-mortem diagnostic tests for bTB in cattle. Using data from a systematic reviewof the scientific literature (published 1934–2009) diagnostic Se and Sp were estimated using Bayesianlogistic regression models adjusting for confounding factors. Random effect terms were used to accountfor unexplained heterogeneity. Parameters in the models were implemented using Markov Chain MonteCarlo (MCMC), and posterior distributions for the diagnostic parameters with adjustment for covariates(confounding factors) were obtained using the inverse logit function. Estimates for Se and/or Sp of thetuberculin skin tests and the IFN- blood test were compared with estimates published 2010–2015.Median Se for the single intradermal comparative cervical tuberculin skin (SICCT) test (standard inter-pretation) was 0.50 and Bayesian credible intervals (CrI) were wide (95% CrI 0.26, 0.78). Median Sp forthe SICCT test was 1.00 (95% CrI 0.99, 1.00). Estimates for the IFN- blood test Bovine Purified ProteinDerivative (PPD)-Avian PPD and Early Secreted Antigen target 6 and Culture Filtrate Protein 10 (ESAT-6/CFP10) ESAT6/CFP10 were 0.67 (95% CrI 0.49, 0.82) and 0.78 (95% CrI 0.60, 0.90) respectively for Se,and 0.98 (95% CrI 0.96, 0.99) and 0.99 (95% CrI 0.99, 1.00) for Sp. The study provides an overview of theaccuracy of a range of contemporary diagnostic tests for bTB in cattle. Better understanding of diagnostictest performance is essential for the design of effective control strategies and their evaluation.The SE3238 project “Meta-analysis of diagnostic tests and modelling to identify appropriate testing strategies to reduce M. bovis infection in GB herds” was funded by the UK Department for Envi-ronment, Food and Rural Affairs (Defra)

Factors Associated with Bovine Neonatal Pancytopenia (BNP) in Calves: A Case-Control Study

Bovine neonatal pancytopenia (BNP; previously known as idiopathic haemorrhagic diathesis and commonly known as bleeding calf syndrome) is a novel haemorrhagic disease of young calves which has emerged in a number of European countries during recent years. Data were retrospectively collected during June to November 2010 for 56 case calves diagnosed with BNP between 17 March and 7 June of the same year. These were compared with 58 control calves randomly recruited from herds with no history of BNP. Multivariable logistic regression analysis showed that increased odds of a calf being a BNP case were associated with its dam having received PregSure® BVD (Pfizer Animal Health) vaccination prior to the birth of the calf (odds ratio (OR) 40.78, p<0.001) and its herd of origin being located in Scotland (OR 9.71, p = 0.006). Decreased odds of a calf being a BNP case were associated with the calf having been kept outside (OR 0.11, p = 0.006). The longer that a cattle herd had been established on the farm was also associated with decreased odds of a calf in that herd being a BNP case (OR 0.97, p = 0.011)

Multicountry survey of emergency and critical care medicine physicians' fluid resuscitation practices for adult patients with early septic shock

Evidence to guide fluid resuscitation evidence in sepsis continues to evolve. We conducted a multicountry survey of emergency and critical care physicians to describe current stated practice and practice variation related to the quantity, rapidity and type of resuscitation fluid administered in early septic shock to inform the design of future septic shock fluid resuscitation trials.Using a web-based survey tool, we invited critical care and emergency physicians in Canada, the UK, Scandinavia and Saudi Arabia to complete a self-administered electronic survey.A total of 1097 physicians responses were included. 1 L was the most frequent quantity of resuscitation fluid physicians indicated they would administer at a time (46.9%, n=499). Most (63.0%, n=671) stated that they would administer the fluid challenges as quickly as possible. Overall, normal saline and Ringers solutions were the preferred crystalloid fluids used often or always in 53.1% (n=556) and 60.5% (n=632) of instances, respectively. However, emergency physicians indicated that they would use normal saline often or always in 83.9% (n=376) of instances, while critical care physicians said that they would use saline often or always in 27.9% (n=150) of instances. Only 1.0% (n=10) of respondents indicated that they would use hydroxyethyl starch often or always; use of 5% (5.6% (n=59)) or 20-25% albumin (1.3% (n=14)) was also infrequent. The majority (88.4%, n=896) of respondents indicated that a large randomised controlled trial comparing 5% albumin to a crystalloid fluid in early septic shock was important to conduct.Critical care and emergency physicians stated that they rapidly infuse volumes of 500-1000 mL of resuscitation fluid in early septic shock. Colloid use, specifically the use of albumin, was infrequently reported. Our survey identifies the need to conduct a trial on the efficacy of albumin and crystalloids on 90-day mortality in patients with early septic shock

COVID-19 collateral: Indirect acute effects of the pandemic on physical and mental health in the UK

ABSTRACTBackgroundConcerns have been raised that the response to the UK COVID-19 pandemic may have worsened physical and mental health, and reduced use of health services. However, the scale of the problem is unquantified, impeding development of effective mitigations. We asked what has happened to general practice contacts for acute physical and mental health outcomes during the pandemic?MethodsUsing electronic health records from the Clinical Research Practice Datalink (CPRD) Aurum (2017-2020), we calculated weekly primary care contacts for selected acute physical and mental health conditions (including: anxiety, depression, acute alcohol-related events, asthma and chronic obstructive pulmonary disease [COPD] exacerbations, cardiovascular and diabetic emergencies). We used interrupted time series (ITS) analysis to formally quantify changes in conditions after the introduction of population-wide restrictions (‘lockdown’) compared to the period prior to their introduction in March 2020.FindingsThe overall population included 9,863,903 individuals on 1st January 2017. Primary care contacts for all conditions dropped dramatically after introduction of population-wide restrictions. By July 2020, except for unstable angina and acute alcohol-related events, contacts for all conditions had not recovered to pre-lockdown levels. The largest reductions were for contacts for: diabetic emergencies (OR: 0.35, 95% CI: 0.25-0.50), depression (OR: 0.53, 95% CI: 0.52-0.53), and self-harm (OR: 0.56, 95% CI: 0.54-0.58).InterpretationThere were substantial reductions in primary care contacts for acute physical and mental conditions with restrictions, with limited recovery by July 2020. It is likely that much of the deficit in care represents unmet need, with implications for subsequent morbidity and premature mortality. The conditions we studied are sufficiently severe that any unmet need will have substantial ramifications for the people experiencing the conditions and healthcare provision. Maintaining access must be a key priority in future public health planning (including further restrictions).FundingWellcome Trust Senior Fellowship (SML), Health Data Research UK.RESULTS IN CONTEXTEvidence before this studyA small study in 47 GP practices in a largely deprived, urban area of the UK (Salford) reported that primary care consultations for four broad diagnostic groups (circulatory disease, common mental health problems, type 2 diabetes mellitus and malignant cancer) declined by 16-50% between March and May 2020, compared to what was expected based on data from January 2010 to March 2020. We searched Medline for other relevant evidence of the indirect effect of the COVID-19 pandemic on physical and mental health from inception to September 25th 2020, for articles published in English, with titles including the search terms (“covid*” or “coronavirus” or “sars-cov-2”), and title or abstracts including the search terms (“indirect impact” or “missed diagnos*” or “missing diagnos*” or “delayed diagnos*” or ((“present*” or “consult*” or “engag*” or “access*”) AND (“reduction” or “decrease” or “decline”)). We found no further studies investigating the change in primary care contacts for specific physical- and mental-health conditions indirectly resulting from the COVID-19 pandemic or its control measures. There has been a reduction in hospital admissions and presentations to accident and emergency departments in the UK, particularly for myocardial infarctions and cerebrovascular accidents. However, there is no published evidence specifically investigating the changes in primary care contacts for severe acute physical and mental health conditions.Added value of this studyTo our knowledge this is the first study to explore changes in healthcare contacts for acute physical and mental health conditions in a large population representative of the UK. We used electronic primary care health records of nearly 10 million individuals across the UK to investigate the indirect impact of COVID-19 on primary care contacts for mental health, acute alcohol-related events, asthma/chronic obstructive pulmonary disease (COPD) exacerbations, and cardiovascular and diabetic emergencies up to July 2020. For all conditions studied, we found primary care contacts dropped dramatically following the introduction of population-wide restriction measures in March 2020. By July 2020, with the exception of unstable angina and acute alcohol-related events, primary care contacts for all conditions studied had not recovered to pre-lockdown levels. In the general population, estimates of the absolute reduction in the number of primary care contacts up to July 2020, compared to what we would expect from previous years varied from fewer than 10 contacts per million for some cardiovascular outcomes, to 12,800 per million for depression and 6,600 for anxiety. In people with COPD, we estimated there were 43,900 per million fewer contacts for COPD exacerbations up to July 2020 than what we would expect from previous years.Implicatins of all the available evidenceWhile our results may represent some genuine reduction in disease frequency (e.g. the restriction measures may have improved diabetic glycaemic control due to more regular daily routines at home), it is more likely the reduced primary care conatcts we saw represent a substantial burden of unmet need (particularly for mental health conditions) that may be reflected in subsequent increased mortality and morbidity. Health service providers should take steps to prepare for increased demand in the coming months and years due to the short and longterm ramifications of reduced access to care for severe acute physical and mental health conditions. Maintaining access to primary care is key to future public health planning in relation to the pandemic.</jats:sec

Indirect acute effects of the COVID-19 pandemic on physical and mental health in the UK: a population-based study.

BACKGROUND: There are concerns that the response to the COVID-19 pandemic in the UK might have worsened physical and mental health, and reduced use of health services. However, the scale of the problem is unquantified, impeding development of effective mitigations. We aimed to ascertain what has happened to general practice contacts for acute physical and mental health outcomes during the pandemic. METHODS: Using de-identified electronic health records from the Clinical Research Practice Datalink (CPRD) Aurum (covering 13% of the UK population), between 2017 and 2020, we calculated weekly primary care contacts for selected acute physical and mental health conditions: anxiety, depression, self-harm (fatal and non-fatal), severe mental illness, eating disorder, obsessive-compulsive disorder, acute alcohol-related events, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, acute cardiovascular events (cerebrovascular accident, heart failure, myocardial infarction, transient ischaemic attacks, unstable angina, and venous thromboembolism), and diabetic emergency. Primary care contacts included remote and face-to-face consultations, diagnoses from hospital discharge letters, and secondary care referrals, and conditions were identified through primary care records for diagnoses, symptoms, and prescribing. Our overall study population included individuals aged 11 years or older who had at least 1 year of registration with practices contributing to CPRD Aurum in the specified period, but denominator populations varied depending on the condition being analysed. We used an interrupted time-series analysis to formally quantify changes in conditions after the introduction of population-wide restrictions (defined as March 29, 2020) compared with the period before their introduction (defined as Jan 1, 2017 to March 7, 2020), with data excluded for an adjustment-to-restrictions period (March 8-28). FINDINGS: The overall population included 9 863 903 individuals on Jan 1, 2017, and increased to 10 226 939 by Jan 1, 2020. Primary care contacts for almost all conditions dropped considerably after the introduction of population-wide restrictions. The largest reductions were observed for contacts for diabetic emergencies (odds ratio 0·35 [95% CI 0·25-0·50]), depression (0·53 [0·52-0·53]), and self-harm (0·56 [0·54-0·58]). In the interrupted time-series analysis, with the exception of acute alcohol-related events (0·98 [0·89-1·10]), there was evidence of a reduction in contacts for all conditions (anxiety 0·67 [0·66-0·67], eating disorders 0·62 [0·59-0·66], obsessive-compulsive disorder [0·69 [0·64-0·74]], self-harm 0·56 [0·54-0·58], severe mental illness 0·80 [0·78-0·83], stroke 0·59 [0·56-0·62], transient ischaemic attack 0·63 [0·58-0·67], heart failure 0·62 [0·60-0·64], myocardial infarction 0·72 [0·68-0·77], unstable angina 0·72 [0·60-0·87], venous thromboembolism 0·94 [0·90-0·99], and asthma exacerbation 0·88 [0·86-0·90]). By July, 2020, except for unstable angina and acute alcohol-related events, contacts for all conditions had not recovered to pre-lockdown levels. INTERPRETATION: There were substantial reductions in primary care contacts for acute physical and mental conditions following the introduction of restrictions, with limited recovery by July, 2020. Further research is needed to ascertain whether these reductions reflect changes in disease frequency or missed opportunities for care. Maintaining health-care access should be a key priority in future public health planning, including further restrictions. The conditions we studied are sufficiently severe that any unmet need will have substantial ramifications for the people with the conditions as well as health-care provision. FUNDING: Wellcome Trust Senior Fellowship, Health Data Research UK

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype