Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Comparison of routine field epidemiology and whole genome sequencing to identify tuberculosis transmission in a remote setting.

Yukon Territory (YT) is a remote region in northern Canada with ongoing spread of tuberculosis (TB). To explore the utility of whole genome sequencing (WGS) for TB surveillance and monitoring in a setting with detailed contact tracing and interview data, we used a mixed-methods approach. Our analysis included all culture-confirmed cases in YT (2005-2014) and incorporated data from 24-locus Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) genotyping, WGS and contact tracing. We compared field-based (contact investigation (CI) data + MIRU-VNTR) and genomic-based (WGS + MIRU-VNTR + basic case data) investigations to identify the most likely source of each person's TB and assessed the knowledge, attitudes and practices of programme personnel around genotyping and genomics using online, multiple-choice surveys (n = 4) and an in-person group interview (n = 5). Field- and genomics-based approaches agreed for 26 of 32 (81%) cases on likely location of TB acquisition. There was less agreement in the identification of specific source cases (13/22 or 59% of cases). Single-locus MIRU-VNTR variants and limited genetic diversity complicated the analysis. Qualitative data indicated that participants viewed genomic epidemiology as a useful tool to streamline investigations, particularly in differentiating latent TB reactivation from the recent transmission. Based on this, genomic data could be used to enhance CIs, focus resources, target interventions and aid in TB programme evaluation.

Whole genome sequencing for improved understanding of Mycobacterium tuberculosis transmission in a remote circumpolar region.

Few studies have used genomic epidemiology to understand tuberculosis (TB) transmission in rural and remote settings - regions often unique in history, geography and demographics. To improve our understanding of TB transmission dynamics in Yukon Territory (YT), a circumpolar Canadian territory, we conducted a retrospective analysis in which we combined epidemiological data collected through routine contact investigations with clinical and laboratory results. Mycobacterium tuberculosis isolates from all culture-confirmed TB cases in YT (2005-2014) were genotyped using 24-locus Mycobacterial Interspersed Repetitive Units-Variable Number of Tandem Repeats (MIRU-VNTR) and compared to each other and to those from the neighbouring province of British Columbia (BC). Whole genome sequencing (WGS) of genotypically clustered isolates revealed three sustained transmission networks within YT, two of which also involved BC isolates. While each network had distinct characteristics, all had at least one individual acting as the probable source of three or more culture-positive cases. Overall, WGS revealed that TB transmission dynamics in YT are distinct from patterns of spread in other, more remote Northern Canadian regions, and that the combination of WGS and epidemiological data can provide actionable information to local public health teams.

Multicentre, blinded, randomised clinical trial comparing the use of flunixin meglumine with firocoxib in horses with small intestinal strangulating obstruction.

BACKGROUND: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo-oxygenases (COX). COX-1 is expressed constitutively and promotes gut barrier function, whereas COX-2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX-2 selective NSAIDs as compared with horses treated with flunixin meglumine. OBJECTIVES: We hypothesised that treatment of post-surgical SISO horses with firocoxib (COX-2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. STUDY DESIGN: Blinded randomised clinical trial. METHODS: In addition to clinical monitoring, preoperative and 12-, 24- and 48-h post-operative plasma samples were assessed for prostaglandin E2 (PGE2 ), thromboxane B2 (TXB2 ), TNF⍺ and soluble CD14 (sCD14). RESULTS: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post-operative period in three university hospitals from 2015 to 2017. COX-2 selectivity was confirmed by a relative lack of inhibition of the COX-1 prostanoid TXB2 by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX-2 prostanoid PGE2 . There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23-fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. MAIN LIMITATIONS: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. CONCLUSIONS: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control.

Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis.

BACKGROUND: Therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes, but there is little evidence to guide TDM in clinical practice. DESIGN: We performed a systematic review and meta-analysis to summarise existing literature on TDM in first-line drugs. RESULTS: We identified 41 studies that reported 2 h post-dose drug concentrations (C2h) for first-line drugs and 12 studies that reported clinical outcomes. We pooled data by study quality, design, region, dosing modality and patient characteristics. The pooled proportion of subjects with low isoniazid C2h was 0.43 (95%CI 0.32-0.55), 0.67 (95%CI 0.60-0.74) had low rifampicin C2h, 0.27 (95%CI 0.17-0.38) had low ethambutol C2h, and 0.12 (95%CI 0.07-0.19) had low pyrazinamide C2h. Patients with diabetes had a non-significant increase in the proportion of subjects with low C2h levels across all four drugs. Only three of 12 studies that examined clinical outcomes demonstrated an association between low C2h and unsuccessful treatment outcomes. CONCLUSION: Across a wide variety of studies, a high proportion of patients undergoing first-line anti-tuberculosis treatment had 2 h drug concentrations below the accepted normal threshold. These findings point to a discrepancy between accepted 2 h TDM thresholds and TB drug dosing recommendations.

Risk of active tuberculosis in chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Although the global prevalence of chronic kidney disease (CKD) is increasing, the relationship between CKD and active TB is not well described. OBJECTIVE: To conduct a systematic review to evaluate active TB risk in CKD populations. METHODS: We searched Ovid Medline, EMBASE and Cochrane databases and relevant journals to identify multicentre or regional studies reporting quantitative effect estimates of an association between CKD and active TB. Risk ratios and rate ratios were used as common measures of association. Pooled estimates were generated using a random-effects model. RESULTS: Of 3406 papers screened, 12 eligible studies were identified with 71,374 end-stage renal disease (ESRD) patients and 560 TB cases. Meta-analysis of adjusted rate ratio data in dialysis populations showed an increased rate of 3.62 (95%CI 1.79-7.33, P < 0.001) compared to the general population, while unadjusted risk ratio data in transplant populations showed an increased risk of 11.35 (95%CI 2.97-43.41) compared to the general population. CONCLUSION: We found consistent evidence of an increased risk of active TB in ESRD compared to the general population. This relationship persisted despite variability in study population, design and renal replacement therapy (RRT) modality. Further research into the role of comorbidities, RRT modality and CKD stage is required to better understand the association between CKD and active TB.

Accuracy of alveolar bone measurements from cone beam computed tomography acquired using varying settings.

OBJECTIVES: To investigate the accuracy and reliability of cone beam computed tomography (CBCT) measurements of buccal alveolar bone height (BBH) and thickness (BBT) using custom acquisition settings. SETTINGS AND SAMPLE POPULATION: School of Dentistry, Oregon Health & Science University. Twelve embalmed cadavers. MATERIALS AND METHODS: Cadaver heads were imaged by CBCT (i-CAT® 17-19, Imaging Sciences International, Hatfield, PA) using a 'long scan' (LS) setting with 619 projection images, 360° revolution, 26.9 s duration, and 0.2 mm voxel size, and using a 'short scan' (SS) setting with 169 projection images, 180° rotation, 4.8 s duration, and 0.3 mm voxel size. BBH and BBT were measured with 65 teeth, indirectly from CBCT images and directly through dissection. Comparisons were assessed using paired t-tests (p≤0.05). Level of agreement was assessed by concordance correlation coefficients, Pearson's correlation coefficients, and Bland-Altman plots. RESULTS: Mean differences in measurements compared to direct measurements were as follows, LS 0.17±0.12 (BBH) and 0.10±0.07 mm (BBT), and SS 0.41±0.32 (BBH) and 0.12±0.11 mm (BBT). No statistical differences were found with any of BBH or BBT measurements. Correlation coefficients and Bland-Altman plots showed agreement was high between direct and indirect measurement methods, although agreement was stronger for measurements of BBH than BBT. CONCLUSIONS: Compared to the LS, the similarity in results with the reduced scan times and hence reduced effective radiation dose, favors use of shorter scans, unless other purposes for higher resolution imaging can be defined.

Chest radiography for active tuberculosis case finding in the homeless: a systematic review and meta-analysis.

SETTING: In low-incidence regions, tuberculosis (TB) often affects vulnerable populations. Guidelines recommend active case finding (ACF) in homeless populations, but there is no consensus on a preferred screening method. OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the use of chest X-ray (CXR) screening in ACF for TB in homeless populations. DESIGN: Articles were identified through EMBASE, Medline and the Cochrane Library. Studies using symptom screens, CXRs, sputum sweeps, tuberculin skin tests and/or interferon-gamma release assays to detect active TB in homeless populations were sought. Data were extracted using a standardised method by two reviewers and validated with an objective tool. RESULTS: Sixteen studies addressing CXR screening of homeless populations for active TB in low-incidence regions were analysed. The pooled prevalence of active TB in the 16 study cohorts was 931 per 100 000 population screened (95%CI 565-1534) and 782/100 000 CXR performed (95%CI 566-1079). Six of seven longitudinal screening programs reported a reduction in regional TB incidence after implementation of the CXR-based ACF programme. CONCLUSION: Our data suggest that CXR screening is a good tool for ACF in homeless populations in low-incidence regions.

Temperature response of denitrification rate and greenhouse gas production in agricultural river marginal wetland soils.

Soils are predicted to exhibit significant feedback to global warming via the temperature response of greenhouse gas (GHG) production. However, the temperature response of hydromorphic wetland soils is complicated by confounding factors such as oxygen (O2 ), nitrate (NO3-) and soil carbon (C). We examined the effect of a temperature gradient (2-25 °C) on denitrification rates and net nitrous oxide (N2 O), methane (CH4 ) production and heterotrophic respiration in mineral (Eutric cambisol and Fluvisol) and organic (Histosol) soil types in a river marginal landscape of the Tamar catchment, Devon, UK, under non-flooded and flooded with enriched NO3- conditions. It was hypothesized that the temperature response is dependent on interactions with NO3--enriched flooding, and the physicochemical conditions of these soil types. Denitrification rate (mean, 746 ± 97.3 µg m(-2)  h(-1) ), net N2 O production (mean, 180 ± 26.6 µg m(-2)  h(-1) ) and net CH4 production (mean, 1065 ± 183 µg m(-2)  h(-1) ) were highest in the organic Histosol, with higher organic matter, ammonium and moisture, and lower NO3- concentrations. Heterotrophic respiration (mean, 127 ± 4.6 mg m(-2)  h(-1) ) was not significantly different between soil types and dominated total GHG (CO2 eq) production in all soil types. Generally, the temperature responses of denitrification rate and net N2 O production were exponential, whilst net CH4 production was unresponsive, possibly due to substrate limitation, and heterotrophic respiration was exponential but limited in summer at higher temperatures. Flooding with NO3- increased denitrification rate, net N2 O production and heterotrophic respiration, but a reduction in net CH4 production suggests inhibition of methanogenesis by NO3- or N2 O produced from denitrification. Implications for management and policy are that warming and flood events may promote microbial interactions in soil between distinct microbial communities and increase denitrification of excess NO3- with N2 O production contributing to no more than 50% of increases in total GHG production.

Therapeutic drug monitoring in the treatment of tuberculosis: a retrospective analysis.

SETTING: Tuberculosis (TB) in-patient treatment unit in Vancouver, Canada. OBJECTIVE: To examine the results of therapeutic drug monitoring (TDM) in anti-tuberculosis treatment. DESIGN: We performed a retrospective analysis of TDM data from 2000 to 2010. All in-patients treated for TB with TDM performed during their treatment course were included. RESULTS: TDM was performed on 52 patients in 76 treatment episodes from 2000 to 2010. Overall, 103/213 (48.4%) drug levels measured were low, and 5/213 (2.3%) were high. At least one drug level was low in 47/52 (90.3%) patients. Initial serum levels were low in respectively 76.6% and 68.4% of isoniazid (INH) and rifampicin (RMP) levels. In contrast, only 2.9% of initial pyrazinamide levels were low. Five patients with a susceptible strain on initial presentation later developed drug-resistant disease, with all five patients demonstrating at least one low drug level and two demonstrating multiple low levels. Dose adjustments were made in response to 26 INH and RMP levels, with variable serum responses. CONCLUSION: In this population with high rates of treatment failure and acquired resistance, we demonstrate that most patients had low drug levels. Prospective studies are required to examine the relationship between drug levels and clinical outcomes.

Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses.

REASONS FOR PERFORMING THE STUDY: Endotoxaemia contributes to morbidity and mortality in horses with colic due to inflammatory cascade activation. Effective therapeutic interventions are limited for these horses. Ethyl pyruvate (EP), an anti-inflammatory agent that alters the expression of proinflammatory cytokines, improved survival and organ function in sepsis and gastrointestinal injury in rodents and swine. Therapeutic efficacy of EP is unknown in endotoxaemic horses. OBJECTIVES: Determine the effects of EP on signs of endotoxaemia and expression of proinflammatory cytokines following administration of lipopolysaccharide (LPS) in horses. METHODS: Horses received 30 ng/kg bwt LPS in saline to induce signs of endotoxaemia. Next, horses received lactated Ringer's solution (LRS), (n = 6), 150 mg/kg bwt EP in LRS, (n = 6), or 1.1 mg/kg bwt flunixin meglumine (FM), (n = 6). Controls received saline followed by LRS (n = 6). Physical examinations, behaviour pain scores and blood for clinical pathological testing and gene expression were obtained at predetermined intervals for 24 h. RESULTS: Lipopolysaccharide infusion produced clinical and clinicopathological signs of endotoxaemia and increased expression of tumour necrosis factor alpha (TNFα), interleukin 6 (IL-6) and IL-8 (P<0.001) compared with controls. Leucopenia and neutropenia occurred in all horses that received LPS. Horses treated with EP and FM had significantly (P<0.0001) reduced pain scores compared with horses receiving LPS followed by LRS. Flunixin meglumine was significantly more effective at ameliorating fever compared with EP. Both EP and FM significantly diminished TNFα expression. Ethyl pyruvate significantly decreased, but FM significantly increased, IL-6 expression. Neither EP nor FM altered IL-8 expression. CONCLUSIONS AND POTENTIAL RELEVANCE: Ethyl pyruvate administered following LPS diminished the clinical effects of endotoxaemia and decreased proinflammatory gene expression in horses. Ethyl pyruvate suppressed expression of proinflammatory cytokines better than FM. However, FM was a superior anti-pyretic compared with EP. Ethyl pyruvate may have therapeutic applications in endotoxaemic horses.

Recommendations on modern contact investigation methods for enhancing tuberculosis control.

Effective contact investigations are paramount to the success of tuberculosis (TB) control in high-risk communities in low TB prevalence countries. National and international guidelines on TB contact investigations are available and vary widely on recommendations. Because of the limitations of traditional contact tracing, new approaches are under investigation, and in some cases in use, to ensure effective TB control in those persons and communities at greatest risk. These non-traditional approaches include the use of social network analysis, geographic information systems and genomics, in addition to the widespread use of genotyping, to better understand TB transmission. Detailed guidelines for the use of these methods during TB outbreaks and in routine follow-up of TB contact investigations do not currently exist despite evidence that they may improve TB control efforts. It remains unclear as to when it is most appropriate and effective to use a network-informed approach alone, or in combination with other methodologies as well as the extent of data collection required to inform practice. TB controllers should consider developing the capacity to facilitate the systematic collection, analysis, and interpretation of contact investigation data using such novel methodologies, particularly in high-risk communities. Further investigation should focus on questionnaire development and adaptation, electronic data management and infrastructure, development of local capability and consultant expertise, and the use of coordinated approaches, including deployment strategies and evaluation.

Is the delay in diagnosis of pulmonary tuberculosis related to exposure to fluoroquinolones or any antibiotic?

BACKGROUND: Delays in diagnosis of tuberculosis (TB) have been associated with previous use of antibiotics, and in particular fluoroquinolones (FQ), for suspected pulmonary infections. METHODS: We conducted a population-based cohort study with 2232 patients who had active TB between 1997 and 2006 (records obtained from the British Columbia Linked Health Databases). Patients with a record of an initial health care contact preceding the diagnosis of TB were identified for inclusion. Health care delay was defined as the time between initial health care contact and the initiation of anti-tuberculosis medication, and was compared between patients prescribed antibiotics and those not exposed to any antibiotics. RESULTS: A total of 1544 patients were included. After adjusting for covariates, average health care delay for patients exposed to antibiotics was found to be significantly greater, by a factor of 2.10 (95%CI 1.80-2.44), with a median delay of 41 days in the antibiotic group compared to 14 days in the non-antibiotic group. Sex, age, foreign-born status and socio-economic status were non-significant factors. Health care delay increased with the number of antibiotic courses received, but not with the type of antibiotic. CONCLUSIONS: Previous treatment with any antibiotic, and not only a FQ, is associated with a delay in TB diagnosis.

Preliminary safety and biological efficacy studies of ethyl pyruvate in normal mature horses.

REASONS FOR PERFORMING THE STUDY: Endotoxaemia causes substantial morbidity and mortality in horses with colic and sepsis. Ethyl pyruvate is a novel anti-inflammatory medication that improved survival in preclinical models of severe sepsis endotoxaemia and intestinal ischaemia and reperfusion in rodents, swine, sheep and dogs and may be a useful medication in horses. HYPOTHESIS: Ethyl pyruvate has no adverse effects in normal horses and is biologically active based on suppression of proinflammatory gene expression in endotoxin stimulated whole blood, in vitro. METHODS: Physical and neurological examinations, behaviour scores, electrocardiograms and clinicopathological tests were performed on 5 normal healthy horses receiving 4 different doses of ethyl pyruvate. Doses included 0, 50, 100 and 150 mg/kg bwt administered in a randomised crossover design with a 2 week washout period between doses. Biological efficacy was assessed by stimulating whole blood with endotoxin from the horses that received ethyl pyruvate prior to and 1 and 6 h after drug infusion. Gene expression for TNFα, IL-1ß and IL-6 was assessed. RESULTS: There were no effects of drug or dose (0, 50, 100 or 150 mg/kg bwt) on any of the physical or neurological examination, behaviour factors, electrocardiogram or clinical pathological results collected from any of the horses. All parameters measured remained within the normal reference range. There was a significant reduction in TNFα, IL-1ß and IL-6 gene expression in endotoxin stimulated whole blood from horses 6 h after receiving 150 mg/kg bwt ethyl pyruvate. There were no detectable effects on gene expression of any of the other doses of ethyl pyruvate tested. CONCLUSION: We were unable to detect any detrimental effects of ethyl pyruvate administration in normal horses. Ethyl pyruvate significantly decreased proinflammatory gene expression in endotoxin stimulated blood 6 h after drug administration. CLINICAL RELEVANCE: Ethyl pyruvate may be a safe, effective medication in endotoxaemic horses.

Ethyl pyruvate diminishes the endotoxin-induced inflammatory response of bovine mammary endothelial cells.

The endotoxin-induced inflammatory response during coliform mastitis is difficult to control with the currently available therapeutics. Endothelial cells are among the first cell type to be engaged in the inflammatory response and can modulate the severity of inflammation by producing proinflammatory mediators upon endotoxin exposure. Ethyl pyruvate, an ethyl ester of pyruvic acid, can ameliorate endotoxin-induced inflammatory responses by inhibiting the production of proinflammatory mediators in several in vitro and in vivo endotoxemia models. The objective of this study was to determine the effect of ethyl pyruvate on the production of vascular proinflammatory mediators that are associated with the pathogenesis of coliform mastitis. The ability of ethyl pyruvate to reduce the expression of proinflammatory mediators was evaluated in cultured bovine mammary endothelial cells (BMEC) stimulated with endotoxin. Treatment of endotoxin-stimulated BMEC with ethyl pyruvate significantly reduced gene expression of IL-6, IL-8, and intercellular adhesion molecule 1 as well as expression of eicosanoid-producing enzymes, including cyclooxygenase 2 and 15-lipoxygenase 1. This is the first time that the effect of ethyl pyruvate was evaluated in an in vitro BMEC model of coliform mastitis. The ability of ethyl pyruvate to effectively inhibit gene and protein expression of potent vascular proinflammatory mediators in vitro warrants further investigations to assess in vivo efficacy. Ethyl pyruvate is safe for human consumption, and it may be an attractive candidate as a therapeutic in ameliorating the severe pathogenesis associated with coliform mastitis.

Helping students become the medical teachers of the future--the Doctors as Teachers and Educators (DATE) Programme of Barts and the London School of Medicine and Dentistry, London.

CONTEXT: In the United Kingdom (UK), learning about teaching is an integral part of the General Medical Council's recommendations for the undergraduate medical curriculum. Yet often, implementing this aspect of learning presents a challenge to curriculum organisers in terms of content, timing and student interest. PROGRAMME OBJECTIVES AND STRUCTURE: The Doctors as Teachers and Educators (DATE) programme was set up at Barts and the London School of Medicine and Dentistry specifically to meet the requirements for development in teaching. Although largely practical, the two-day programme offers an introduction to educational theory and the teaching requirements for junior doctors in training. The methods used are lectures and group work within plenary sessions, followed by small group micro-teaching sessions. The DATE programme has now been undertaken by over 900 graduates. EVALUATION METHODS: We evaluated the Date programme by means of end-of-course questionnaires completed by two cohorts of students during the 2007/8 academic year and through the use of Nominal Group Technique in 2008/9. In line with the goals of the evaluation, the data on students' views were analysed to elicit self-reported learning and develop the programme. RESULTS: Response rates of the two cohorts to the surveys were high (80% and 98%). Nearly 100% of the students reported through the survey that they had gained confidence in teaching. In the nominal groups, students indicated that they had gained insight into educational principles like student-centredness and gained an appreciation for the nature of educational evidence and scholarship. They challenged the curriculum organisers to achieve an appropriate balance between theory and practice. CONCLUSIONS: A programme about teaching at the undergraduate medical level can be well-received by students; the DATE model could be transferred to other international contexts.

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity.

Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(-2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.

Use of ultrasound to evaluate outcome following colic surgery for equine large colon volvulus.

REASONS FOR PERFORMING STUDY: The post operative response of the large colon wall after a surgically corrected large colon volvulus (LCV) has not been investigated. OBJECTIVES: To use transabdominal ultrasound to monitor the post operative change in large colon wall thickness following surgical correction of LCV. HYPOTHESIS: A prolonged period to colon wall involution is correlated with an increased rate of post operative morbidity and mortality. METHODS: A prospective clinical study including horses that presented to the North Carolina State University Veterinary Teaching Hospital for colic between September 2006 and March, 2008, had surgically diagnosed and corrected LCV (at least 360 degrees ) without resection and recovered from anaesthesia. Ultrasound of the ventral large colon was performed at the time of anaesthetic recovery and every 6-8 h until the colon wall returned to normal thickness (< or = 5 mm). Outcome was evaluated using a one-way ANOVA to compare average time to colon wall involution between: 1) survivors and nonsurvivors; and 2) horses that developed multiple organ dysfunction syndrome (MODS) during the post operative period and those that recovered without evidence of MODS. RESULTS: Sixteen horses that recovered without evidence of MODS had a significantly shorter period to colon wall involution (< or = 5 mm) compared to those diagnosed with MODS (mean +/- s.e. 19.6 h +/- 2.5 and 39.7 h +/- 6.7 respectively, P = 0.006). There was no significant difference in mean period to colon wall involution between survivors and nonsurvivors (26.2 +/- 4.9 and 33.2 +/- 7.8 h, respectively). CONCLUSIONS: A shorter time to colon wall involution was associated with decreased post operative morbidity in horses presented for surgical correction of large colon volvulus without resection. POTENTIAL RELEVANCE: Ultrasonographic monitoring of colon wall involution after surgical correction of LCV may aid in identifying those cases at risk of MODS. Further investigation of colon wall involution time using a larger number of horses is warranted.