Non-specialist emergency medicine qualifications in Africa: Lessons from the South African Diploma in Primary Emergency Care.

Introduction: Non-specialist emergency medicine qualifications are an important step in developing the specialty of emergency medicine. The Diploma in Primary Emergency Care (Dip PEC) of the Colleges of Medicine of South Africa is one of the oldest registrable qualifications. Reviewing its changing role over time has lessons for academics developing Emergency Medicine training in Africa. Methods: Through a series of meetings and stakeholder engagements, the Council of the College of Emergency Medicine conducted a three year review of the qualification focusing on the curriculum, assessment processes, success rate and role of the qualification in the South African medical context. A survey of the perceptions of graduates over the last six years was also conducted. Results: The survey showed candidate numbers increased dramatically from 2011 to 2017, resulting in an entry cap. Lessons identified included ensuring that the qualification is responsive to the state of development of emergency medicine in the country, needing aligned and valid assessment processes and maintaining the value of the qualification in context. Discussion: Emergency medicine qualifications are dynamic in and of themselves and how they relate to their context. Program designers must prioritize ongoing evaluation from the start.

Effectiveness of a quality improvement collaborative in reducing time to surgery for patients requiring emergency cholecystectomy.

Background: Acute gallstone disease is a high-volume emergency general surgery presentation with wide variations in the quality of care provided across the UK. This controlled cohort evaluation assessed whether participation in a quality improvement collaborative approach reduced time to surgery for patients with acute gallstone disease to fewer than 8 days from presentation, in line with national guidance. Methods: Patients admitted to hospital with acute biliary conditions in England and Wales between 1 April 2014 and 31 December 2017 were identified from Hospital Episode Statistics data. Time series of quarterly activity were produced for the Cholecystectomy Quality Improvement Collaborative (Chole-QuIC) and all other acute National Health Service hospitals (control group). A negative binomial regression model was used to compare the proportion of patients having surgery within 8 days in the baseline and intervention periods. Results: Of 13 sites invited to join Chole-QuIC, 12 participated throughout the collaborative, which ran from October 2016 to January 2018. Of 7944 admissions, 1160 patients had a cholecystectomy within 8 days of admission, a significant improvement (P < 0·050) from baseline performance. This represented a relative change of 1·56 (95 per cent c.i. 1·38 to 1·75), compared with 1·08 for the control group. At the individual site level, eight of the 12 Chole-QuIC sites showed a significant improvement (P < 0·050), with four sites increasing their 8-day surgery rate to over 20 per cent of all emergency admissions, well above the mean of 15·3 per cent for control hospitals. Conclusion: A surgeon-led quality improvement collaborative approach improved care for patients requiring emergency cholecystectomy.

Antecedentes: La patología biliar aguda litiásica es una de las urgencias con más volumen de casos en cirugía general, con amplias variaciones en la calidad de la atención prestada en todo el Reino Unido. En este estudio de cohortes controlado se valoró si la participación en un enfoque colaborativo de mejora de la calidad disminuía el tiempo hasta la cirugía en pacientes con patología biliar aguda litiásica a menos de 8 días desde la presentación, de acuerdo con la guía nacional. Métodos: Se identificó a los pacientes que precisaron un ingreso hospitalario por patología biliar aguda en Inglaterra y Gales, del 1 de abril de 2014 al 31 de diciembre de 2017, a partir de datos de las estadísticas de episodios hospitalarios. Se crearon series temporales de actividad trimestral para Chole­QuIC y para todos los demás hospitales de agudos del NHS (grupo control). Se utilizó un modelo de regresión binomial negativa para comparar la proporción de pacientes sometidos a cirugía dentro de los primeros 8 días en los periodos basal y de intervención. Resultados: De los 13 sitios invitados a unirse a Chole­QuIC, 12 participaron durante toda la colaboración, que se desarrolló entre octubre de 2016 y enero de 2018. De los 7.944 ingresos, en 1.160 pacientes se realizó la colecistectomía dentro de los 8 días posteriores a su ingreso, una mejora significativa (P < 0,05) en comparación con el periodo previo a la intervención. Esto representó un cambio relativo de 1,56 (i.c. del 95%: 1,38 a 1,75) en comparación con 1,08 para el grupo de control. A nivel de cada uno de los hospitales, ocho de los 12 centros Chole­QuIC presentaron una mejora significativa (P < 0,05), y en cuatro de ellos el porcentaje de cirugía en 8 días aumentó a más del 20% de todos los ingresos urgentes, muy por encima del promedio de 15,3% para hospitales de control. Conclusión: Un enfoque colaborativo de mejora de la calidad dirigido por el cirujano mejoró la atención a los pacientes que precisan una colecistectomía urgente.

Correction to: Improving care at scale: process evaluation of a multi-component quality improvement intervention to reduce mortality after emergency abdominal surgery (EPOCH trial).

Following the publication of this article [1], the authors reported a number of errors which are given below.

Improving care at scale: process evaluation of a multi-component quality improvement intervention to reduce mortality after emergency abdominal surgery (EPOCH trial).

BACKGROUND: Improving the quality and safety of perioperative care is a global priority. The Enhanced Peri-Operative Care for High-risk patients (EPOCH) trial was a stepped-wedge cluster randomised trial of a quality improvement (QI) programme to improve 90-day survival for patients undergoing emergency abdominal surgery in 93 hospitals in the UK National Health Service. METHODS: The aim of this process evaluation is to describe how the EPOCH intervention was planned, delivered and received, at both cluster and local hospital levels. The QI programme comprised of two interventions: a care pathway and a QI intervention to aid pathway implementation, focussed on stakeholder engagement, QI teamwork, data analysis and feedback and applying the model for improvement. Face-to-face training and online resources were provided to support senior clinicians in each hospital (QI leads) to lead improvement. For this evaluation, we collated programme activity data, administered an exit questionnaire to QI leads and collected ethnographic data in six hospitals. Qualitative data were analysed with thematic or comparative analysis; quantitative data were analysed using descriptive statistics. RESULTS: The EPOCH trial did not demonstrate any improvement in survival or length of hospital stay. Whilst the QI programme was delivered as planned at the cluster level, self-assessed intervention fidelity at the hospital level was variable. Seventy-seven of 93 hospitals responded to the exit questionnaire (60 from a single QI lead response on behalf of the team); 33 respondents described following the QI intervention closely (35%) and there were only 11 of 37 care pathway processes that > 50% of respondents reported attempting to improve. Analysis of qualitative data suggests QI leads were often attempting to deliver the intervention in challenging contexts: the social aspects of change such as engaging colleagues were identified as important but often difficult and clinicians frequently attempted to lead change with limited time or organisational resources. CONCLUSIONS: Significant organisational challenges faced by QI leads shaped their choice of pathway components to focus on and implementation approaches taken. Adaptation causing loss of intervention fidelity was therefore due to rational choices made by those implementing change within constrained contexts. Future large-scale QI programmes will need to focus on dedicating local time and resources to improvement as well as on training to develop QI capabilities. EPOCH TRIAL REGISTRATION: ISRCTN80682973 https://doi.org/10.1186/ISRCTN80682973 Registered 27 February 2014 and Lancet protocol 13PRT/7655.

Closing the theory to practice gap for newly qualified doctors: evaluation of a peer-delivered practical skills training course for newly qualified doctors in preparation for clinical practice.

PURPOSE: The Good Intern Programme (GIP) in Sri Lanka has been implemented to bridge the 'theory to practice gap' of doctors preparing for their internship. This paper evaluates the impact of a 2-day peer-delivered Acute Care Skills Training (ACST) course as part of the GIP. STUDY DESIGN: The ACST course was developed by an interprofessional faculty, including newly graduated doctors awaiting internship (pre-intern), focusing on the recognition and management of common medical and surgical emergencies. Course delivery was entirely by pre-intern doctors to their peers. Knowledge was evaluated by a pre- and post-course multiple choice test. Participants' confidence (post-course) and 12 acute care skills (pre- and post-course) were assessed using Likert scale-based questions. A subset of participants provided feedback on the peer learning experience. RESULTS: Seventeen courses were delivered by a faculty consisting of eight peer trainers over 4 months, training 320 participants. The mean (SD) multiple choice questionnaire score was 71.03 (13.19) pre-course compared with 77.98 (7.7) post-course (p<0.05). Increased overall confidence in managing ward emergencies was reported by 97.2% (n=283) of respondents. Participants rated their post-course skills to be significantly higher (p<0.05) than pre-course in all 12 assessed skills. Extended feedback on the peer learning experience was overwhelmingly positive and 96.5% would recommend the course to a colleague. CONCLUSIONS: A peer-delivered ACST course was extremely well received and can improve newly qualified medical graduates' knowledge, skills and confidence in managing medical and surgical emergencies. This peer-based model may have utility beyond pre-interns and beyond Sri Lanka.

Patient and system factors of mortality after hip fracture: a scoping review.

BACKGROUND: Several patient and health system factors were associated with the risk of death among patients with hip fracture. However, without knowledge of underlying mechanisms interventions to improve survival post hip fracture can only be designed on the basis of the found statistical associations. METHODS: We used the framework developed by Arksey and O'Malley and Levac et al. for synthesis of factors and mechanisms of mortality post low energy hip fracture in adults over the age of 50 years, published in English, between September 1, 2009 and October 1, 2014 and indexed in MEDLINE. Proposed mechanisms for reported associations were extracted from the discussion sections. RESULTS: We synthesized the evidence from 56 articles that reported on 35 patient and 9 system factors of mortality post hip fracture. For 21 factors we found proposed biological mechanisms for their association with mortality which included complications, comorbidity, cardiorespiratory function, immune function, bone remodeling and glycemic control. CONCLUSIONS: The majority of patient and system factors of mortality post hip fracture were reported by only one or two articles and with no proposed mechanisms for their effects on mortality. Where reported, underlying mechanisms are often based on a single article and should be confirmed with further study. Therefore, one cannot be certain whether intervening on such factors may produce expected results.

Electroencephalographic features of moyamoya in adults.

OBJECTIVE: Electroencephalography is useful for evaluating transient neurological events in the setting of moyamoya disease. METHODS: EEG findings of adults with moyamoya seen at a large moyamoya referral center are summarized. Patients were identified by retrospective chart review. RESULTS: EEGs were ordered after cerebral revascularization for altered mental status, aphasia, limb shaking, or facial twitching. Among the study population of 103 patients having EEGs, 24% of adults with moyamoya had a history of clinical seizures. Ischemic or hemorrhagic strokes were associated with a twofold relative risk of seizures. Overall, 90% of EEGs were abnormal, most commonly focally (78%), or diffusely slow (68%). Epileptiform EEG discharges were seen in 24%. Whereas hemispheres with an ischemic stroke had a 19% risk of epileptiform discharges and an 8% risk of seizures on EEG, hemispheres with hemorrhagic stroke had a 35% risk of epileptiform discharges and 19% risk of seizures on EEG. Focal amplitude attenuation was seen in 19%, breach rhythm in 15%, rhythmic delta in 14%, and electrographic seizures in 12%. CONCLUSIONS: Seizures and epileptiform EEG changes are common in patients with moyamoya disease. SIGNIFICANCE: Transient events in patients with moyamoya can result from seizures as well as ischemia.

Segmented interlocking nail: an in vivo evaluation of a novel humeral osteotomy fixation device in a caprine model.

OBJECTIVES: To describe a novel humeral fixation device, the insertion technique, healing of humeral osteotomies, and clinical outcomes in a caprine model over a six month period. METHODS: Fourteen mature female Boer/Nubian cross goats with a mean body weight of 50.7 kg were implanted with a proprietary segmented interlocking nail (SILN) in both humeri. Each goat had one humerus randomly selected for mid-diaphyseal osteotomy. RESULTS: Immediately after surgery all but one goat was able to stand, although none of the goats were weight bearing on the osteotomy limb. During the six month study, clinical lameness was always associated with the osteotomy limb. One month after surgery, lameness for twelve of the goats was grade 2/5 or better. At three months, 11 of the 14 did not exhibit any signs of lameness. On radiographic images, notable malalignment of the osteotomy was observed, although all osteotomies went to bone union. CLINICAL SIGNIFICANCE: The results of this study suggest that despite misalignment, the SILN maintained adequate osteotomy fixation to achieve bone union in the research model studied, with reduced morbidity and early return to function with bilateral implantation. The SILN used in this study allowed intramedullary fixation of humeral diaphyseal osteotomies with a limited and safe surgical approach.

Effects of long- or short-haul transportation of slaughter heifers and cattle liner microclimate on hide contamination with Escherichia coli O157.

Effects of cattle transportation on hide contamination with Escherichia coli O157 have been variable, and the present study was designed to clarify relationships among duration of transport, microclimate, and environment within the trailer and contamination of hides with E. coli O157. Crossbred Angus heifers from a feedlot in southern Alberta were sorted into 10 replicate loads containing 45 animals (short haul, 621.5 ± 2.1 kg of body weight) or 46 animals (long haul, 576.0 ± 1.7 kg of body weight). Long-haul trips (n = 5) were made in July and August to slaughter plant A, whereas short-haul trips (n = 5) were made in October to slaughter plant B. The same trailer unit and driver were used for all loads. Data loggers were located in the ceiling of each compartment of the trailers to record ambient temperature and relative humidity. Each heifer was swabbed on the perineum on-farm prior to loading and immediately after stunning at the slaughter plant (an average 12-h transport for long haul and 1-h transport for short haul). Swabs were transported on ice before immunomagnetic separation for detection of E. coli O157. Transportation did not affect prevalence of hide contamination with E. coli O157, although 80% of long-haul swabs were positive on-farm compared with 26% of short-haul swabs, due to seasonality of shedding E. coli O157. Cattle transported in the nose compartment had fewer positive hide swabs (P < 0.05) than cattle in the deck or belly compartments during long-haul trips, even though the nose had a higher (P < 0.05) temperature-humidity index than the other compartments. Prevalence of hide contamination varied widely among loads even when the organism was at seasonally low levels. This suggests that the feedlot pen has a greater effect on hide contamination at the slaughter plant than transportation factors including temperature-humidity index, loading density, and duration of transport.

Use of model super-shedders to define the role of pen floor and hide contamination in the transmission of Escherichia coli O157:H7.

Super-shedders, cattle shedding at least 10(4) cfu of Escherichia coli O157:H7 per gram of feces, increase the risks of contaminating the food chain and disseminating the organism through cattle populations. Because detecting super-shedders in cattle populations is laborious and time-consuming, a study was conducted to evaluate the role of hide and pen-floor contamination by model super shedders (MSS) in transmission of E. coli O157:H7. Steers (n = 48) negative for E. coli O157:H7 were allocated to 6 pens, with 2 replicate pens per treatment. Treatment A consisted of 3,000 g of feces inoculated with 10(6) cfu/g of a 5-strain mixture of nalidixic acid-resistant E. coli O157:H7 and spread in simulated fecal pats on the pen floor for d 0 through 4 and d 14 through 18. For treatment B, 100 g of the feces per day was spread on the perineum of 1 MSS per pen, and the remaining feces was placed on the pen floor as fecal pats similar to treatment A. Treatment C differed from B in that 50 g of feces was spread on the perineum and 50 g on the brisket of the MSS steer. Fecal samples, perineal swabs (500-cm(2) area around the anus), freshly voided fecal pats and manila rope samples were collected during a 56-d experimental period. More positive rope samples were found in treatments B and C compared with A (P = 0.05), and steers within treatments B and C were 1.3 times more likely (P = 0.05) to shed E. coli O157:H7 in their feces than steers in treatment A. Even though the number of E. coli O157:H7 introduced into pens was similar, results indicate an increased importance of hide compared with pen-floor contamination for transmission of this organism to cattle. Because cattle within treatment B were persistently colonized with E. coli O157:H7, this design should prove suitable for future studies investigating the role of super-shedders in the transmission of E. coli O157:H7.

Oral delivery systems for encapsulated bacteriophages targeted at Escherichia coli O157:H7 in feedlot cattle.

Bacteriophages are natural predators of bacteria and may mitigate Escherichia coli O157:H7 in cattle and their environment. As bacteriophages targeted to E. coli O157:H7 (phages) lose activity at low pH, protection from gastric acidity may enhance efficacy of orally administered phages. Polymer encapsulation of four phages, wV8, rV5, wV7, and wV11, and exposure to pH 3.0 for 20 min resulted in an average 13.6% recovery of phages after release from encapsulation at pH 7.2. In contrast, untreated phages under similar conditions had a complete loss of activity. Steers (n = 24) received 10(11) CFU of naladixic acid-resistant E. coli O157:H7 on day 0 and were housed in six pens of four steers. Two pens were control (naladixic acid-resistant E. coli O157:H7 only), and the remaining pens received polymer-encapsulated phages (Ephage) on days -1, 1, 3, 6, and 8. Two pens received Ephage orally in gelatin capsules (bolus; 10(10) PFU per steer per day), and the remaining two pens received Ephage top-dressed on their feed (feed; estimated 10(11) PFU per steer per day). Shedding of E. coli O157:H7 was monitored for 10 weeks by collecting fecal grab and hide swab samples. Acceptable activity of mixed phages at delivery to steers was found for bolus and feed, averaging 1.82 and 1.13 x 10(9) PFU/g, respectively. However, Ephage did not reduce shedding of naladixic acid-resistant E. coli O157:H7, although duration of shedding was reduced by 14 days (P < 0.1) in bolus-fed steers as compared with control steers. Two successful systems for delivery of Ephage were developed, but a better understanding of phage-E. coli O157:H7 ecology is required to make phage therapy a viable strategy for mitigation of this organism in feedlot cattle.

Effect of rumen protozoa on Escherichia coli O157:H7 in the rumen and feces of specifically faunated sheep.

The effects of rumen protozoal populations on ruminal populations and fecal shedding of Escherichia coli O157:H7 were evaluated by using specifically faunated sheep. Nine fauna-free sheep (three animals per treatment) were inoculated with Dasytricha spp. (DAS sheep); with mixed population A (PopA) comprising Entodinium spp., Isotricha spp., Diplodinium spp., and Polyplastron spp.; or with mixed population B (PopB) comprising Entodinium spp., Isotricha spp., Dasytricha spp., and Epidinium spp.; six sheep were maintained fauna-free (FF sheep) to serve as controls. Sheep were fed barley silage-based diets, and treatment groups were housed in isolated rooms. Sheep were inoculated orally with 10(10) CFU of a four-strain mixture of nalidixic acid-resistant E. coli O157:H7. Samples of ruminal fluid and feces were collected over 77 days. Polyplastron spp. were detected in only one sheep in PopA, and Dasytricha spp. were detected only once within the PopB cohort. Sheep in the DAS group were 2.03 times more likely (P < 0.001) to shed E. coli O157:H7 than were those in the other three treatments, whereas the PopB sheep were less likely (0.65; P < 0.05) to shed this bacterium. The likelihood of harboring ruminal E. coli O157:H7 also tended (P = 0.06) to be higher in DAS and was lower (P < 0.01) in FF than in other cohorts. Possibly, Dasytricha spp. had a hosting effect, and Epidinium spp. had a predatory relationship, with E. coli O157:H7. Additional study into predator-prey and hosting relationships among rumen protozoa and E. coli O157:H7 is warranted.

Spoilage and safety characteristics of ground beef treated with lactic acid bacteria.

Lactic acid bacteria (LAB) can decrease numbers of Escherichia coli O157:H7 and Salmonella in ground beef during storage. Two dose-titration studies were conducted in ground beef to determine dose levels of LAB needed to inhibit the pathogens. A second study evaluated whether LAB masked changes typically associated with the spoilage of ground beef displayed under refrigerated (0 degrees C) or abusive (10 degrees C) temperatures packaged in both traditional overwrap (TOP) and modified atmosphere packaging (MAP; 80% O(2)-20% CO(2)). Microbial analyses were conducted to determine spoilage endpoints and pathogen reduction. In the dose-titration study, Salmonella was reduced by 3 log cycles at all doses (10(6), 10(7), and 10(8) LAB per g) after 3 days of storage and was eliminated after 5 days of storage. E. coli O157:H7 was reduced by 2 log cycles at all dosages after 3 days of storage and by 3 log cycles after 5 days of storage. In the spoilage studies, as expected, total aerobic plate counts and LAB populations in LAB-inoculated samples were higher than the controls initially, but the counts were similar near the end of the study. While total spoilage bacteria generally increased over time, very few differences existed between treatments stored at 0 degrees C and 10 degrees C in coliforms, Brochothrix thermosphacta, yeasts and molds, and Pseudomonas spp. counts for both the TOP and MAP samples. We conclude that LAB could potentially be added to ground beef in TOP and MAP as a processing intervention for E. coli O157:H7 and Salmonella without masking microbial spoilage characteristics.

Perineal swabs reveal effect of super shedders on the transmission of Escherichia coli O157:H7 in commercial feedlots.

Cattle that shed more than 10(4) cfu/g of Escherichia coli O157 in feces have been described as super shedders (SS) and are thought to have major impacts on prevalence and transmission of this organism. Two Southern Alberta commercial feedlots (feedlot X, 7 pens averaging 183 steers; feedlot Y, 5 pens averaging 153 steers) were sampled from May 2007 to January 2008. Background samples [fecal pat (FP) water, ropes] were taken weekly from each pen for 2 wk before collection of samples from individuals [fecal grab (FG); perineal swab] at 2 different times [during spring and summer (S1); immediately before slaughter during fall and winter (S2)]. Immunomagnetic separation and selective media were used for detecting E. coli O157:H7. Positive FG and FP were enumerated by direct plating onto sorbitol MacConkey agar supplemented with 2.5 mg/L of potassium tellurite and 0.05 mg/L of cefixime. Five sorbitol-negative colonies were agglutinated using an anti-O157 latex kit, and the proportion of positive colonies was adjusted for non-E. coli O157:H7. Overall, there were 153 (7.16%) and 10 (0.45%) SS at S1 and S2, respectively. In feedlot X, SS and penmates of SS during S1 were more likely (P < 0.01) to shed E. coli O157:H7 in their feces and have this organism on their perineum than cattle in a pen where no SS were identified. In feedlot Y, SS and penmates of SS during S1 were more likely (P < 0.01) to have E. coli O157:H7 on their perineum than those from a pen where only 1 SS was identified, but steers in only 1 pen with multiple SS were more likely (P < 0.01) to shed this organism in feces. Overall, E. coli O157:H7 was 1.85 times more likely (P < 0.01) to be detected in perineal swabs compared with FG and E. coli O157:H7 was more likely (P < 0.01) to be detected at S1 compared with S2 for all sample types. Super shedders were a larger proportion of shedding cattle in S1 than in S2, but the presence of SS increased (P < 0.01) prevalence of this organism on the perineum of cattle throughout the year. Even when SS did not increase fecal shedding of E. coli O157:H7, their presence increased contamination of hides, an outcome that could have important implications for contamination of carcasses at the abattoir.

HIV/AIDS, STIs and condom use beliefs among male prison inmates in two South African provinces: Mpumalanga and KwaZulu-Natal.

The purpose of this study was to describe the characteristics of a random sample of prison inmates from two provinces in South Africa with respect to correct knowledge regarding HIV/AIDS and sexual transmitted infection (STI) risk and beliefs about condom use. This cross-sectional descriptive study of 357 prison inmates formed part of a larger longitudinal investigation designed to implement a health education intervention for prison inmates in the KwaZulu-Natal (KZN) and Mpumalanga (MP) provinces of South Africa. Mean differences for groups were compared across sites using Analysis of Variance (ANOVA). Inmates from KZN were less likely to agree that 'It is important to use condoms every time you have sex' F (1355) = 25.8, p<0.0001 when compared with inmates in MP. However, they were more likely to agree that 'Condoms work well to prevent the spread of HIV' F (1355) = 11.7, p<0.001; 'Condoms also prevent pregnancy' F (1355) = 5.1, p<0.05. Overall, the demonstrated differences in condom use behaviour suggested that future prevention efforts focus on the importance of using condoms to prevent the spread of HIV/AIDS and other STIs.

Prevalence and impact of bacteriophages on the presence of Escherichia coli O157:H7 in feedlot cattle and their environment.

The relationship between endemic bacteriophages infecting E. coli O157:H7 (referred to as "phage") and levels of shedding of E. coli O157:H7 by cattle was investigated in two commercial feedlots in southern Alberta, Canada. Between May and November 2007, 10 pens of cattle were monitored by collection of pooled fecal pats, water with sediment from troughs, manure slurry from the pen floor, and rectal fecal samples from individual animals (20 per pen) at two separate times. Bacteriophages infecting E. coli O157:H7 were detected more frequently (P<0.001) after 18 to 20 h enrichment than by initial screening and were recovered in 239 of 855 samples (26.5% of 411 pooled fecal pats, 23.8% of 320 fecal grab samples, 21.8% of 87 water trough samples, and 94.6% of 37 pen floor slurry samples). Overall, prevalence of phage was highest (P<0.001) in slurry. Recovery of phage from pooled fecal pats was highest (P<0.05) in May. Overall recovery did not differ (P>0.10) between fecal grab samples and pooled fecal pats. A higher prevalence of phage in fecal pats or water trough samples was associated (P<0.01) with reduced prevalence of E. coli O157:H7 in rectal fecal samples. There was a weak but significant negative correlation between isolation of phage and E. coli O157:H7 in fecal grab samples (r= -0.11; P<0.05). These data demonstrate that the prevalence of phage fluctuates in a manner similar to that described for E. coli O157:H7. Phage were more prevalent in manure slurry than other environmental sources. The likelihood of fecal shedding of E. coli O157:H7 was reduced if cattle in the pen harbored phage.

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer.

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49+/-11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens.

Comparison of fecal versus rectoanal mucosal swab sampling for detecting Escherichia coli O157:H7 in experimentally inoculated cattle used in assessing bacteriophage as a mitigation strategy.

This study was conducted to compare fecal grab (FEC) and rectoanal mucosal swab (RAMS) techniques as sampling methods for surveillance of Escherichia coli O157:H7 in conjunction with administration of a mitigation therapy. The study was nested within a larger experiment that investigated bacteriophage as a preharvest strategy for controlling E. coli O157:H7 in feedlot steers. Samples (FEC and RAMS) were collected from 16 of the 32 feedlot steers (control and oral bacteriophage treatment; n = 8) involved in the mitigation study. All steers had been inoculated on day 0 with 10(10) CFU of nalidixic acid-resistant E. coli O157:H7, and samples were collected on 16 occasions over the next 83 days. FEC samples were assessed by direct plating of serial dilutions in PBS, plus a 6-h enrichment and immunomagnetic separation when E. coli O157:H7 concentrations were below limits detectable by direct plating (i.e., <1 log CFU/g). All RAMS samples were assessed by enrichment and immunomagnetic separation. E. coli O157:H7 was detected more frequently (P < 0.01) by FEC than by RAMS. Overall, 213 of 256 samples were positive either by FEC or RAMS. Discrepancies between sampling techniques were observed in 63 of the 213 positive samples; FEC missed 11 samples that were positive by RAMS, and RAMS missed 52 of those positive by FEC (miss rates of 5.16 and 24.41%, respectively). Kappa values (0.36 to 0.45) indicated only fair to moderate agreement between FEC and RAMS results, but this agreement was higher at lower levels of E. coli O157:H7 shedding (later in the experimental period). Selection of sampling procedure could significantly influence the assessed merit during testing of potential strategies for controlling E. coli O157:H7 on the farm.