Clinical management of high-output stoma: a systematic literature review and meta-analysis.

PURPOSE: High output is a common complication after stoma formation. Although the management of high output is described in the literature, there is a lack of consensus on definitions and treatment. Our aim was to review and summarise the current best evidence. METHODS: MEDLINE, Cochrane Library, BNI, CINAHL, EMBASE, EMCARE, and ClinicalTrials.gov were searched from 1 Jan 2000 to 31 Dec 2021 for relevant articles on adult patients with a high-output stoma. Patients with enteroatmospheric fistulas and case series/reports were excluded. Risk of bias was assessed using RoB2 and MINORS. The review was registered in PROSPERO (CRD42021226621). RESULTS: The search strategy identified 1095 articles, of which 32 studies with 768 patients met the inclusion criteria. These studies comprised 15 randomised controlled trials, 13 non-randomised prospective trials, and 4 retrospective cohort studies. Eighteen different interventions were assessed. In the meta-analysis, there was no difference in stoma output between controls and somatostatin analogues (g - 1.72, 95% CI - 4.09 to 0.65, p = 0.11, I2 = 88%, t2 = 3.09), loperamide (g - 0.34, 95% CI - 0.69 to 0.01, p = 0.05, I2 = 0%, t2 = 0) and omeprazole (g - 0.31, 95% CI  - 2.46 to 1.84, p = 0.32, I2 = 0%, t2 = 0). Thirteen randomised trials showed high concern of bias, one some concern, and one low concern. The non-randomised/retrospective trials had a median MINORS score of 12 out of 24 (range 7-17). CONCLUSION: There is limited high-quality evidence favouring any specific widely used drug over the others in the management of high-output stoma. Evidence, however, is weak due to inconsistent definitions, risk of bias and poor methodology in the existing studies. We recommend the development of validated core descriptor and outcomes sets, as well as patient-reported outcome measures.

Clinician preferences in the treatment of acutely symptomatic hernia: the 'MASH' survey.

INTRODUCTION: There is limited high-quality evidence to guide the management of acute hernia presentation. The aim of this study was to survey surgeons to assess current trends in assessment, treatment strategy and operative decisions in the management of acutely symptomatic hernia. METHODS: A survey was developed with reference to current guidelines, and reported according to Checklist for Reporting Results of Internet E-Surveys guidelines. Ethical approval was obtained from the University of Sheffield (UREC:034047). The survey explored practice in groin, umbilical/paraumbilical and incisional hernia presenting acutely. It captured respondent demographics, and preferences for investigations, treatment strategies and repair techniques for each hernia type, using a five-point Likert scale. RESULTS: Some 145 responses were received, of which 39 declared a specialist hernia practice. Essential investigations included urea and electrolytes (58.6%) and inflammatory markers (55.6%). Computed tomography scan of the abdomen was essential for assessment of incisional hernia (90.9%), but not for other hernia types. Bowel compromise drives early surgery, and increasing American Society of Anesthesiology score pushes towards non-operative management. Type of repair was driven by hernia contents, with increasing contamination associated with increased rates of suture repair. Where mesh was proposed in contaminated settings, biological types were preferred. There was variation in the potential use of laparoscopy for groin hernia. CONCLUSIONS: This survey provides a snapshot of current trends in the management of acutely symptomatic hernia. It demonstrates variation across aspects of assessment and repair technique. Additional data are required to inform practice in these areas.

Benchmarking total knee replacement constructs using noninferiority analysis: the New Zealand joint registry study.

BACKGROUND: The aim of this study was to compare the relative performance of total knee replacement constructs and discern if there is variability in performance in currently commonly used prostheses in the New Zealand Joint Registry (NZJR) using a noninferiority analysis. METHODS: All patients who underwent a primary total knee replacement (TKR) registered in the NZJR between 1st January 1999 to June 2020 were identified. Using a noninferiority analysis, the performance of total knee replacement prostheses were compared with the best performing contemporary construct. Construct all-cause revision rate was estimated using the 1-Kaplan Meier survival function method to estimate net failure. The difference in all-cause revision rates between the contemporary benchmark and all other constructs was tested. RESULTS: In total 110 183 TKR were recorded and 25 constructs (102 717 procedures) had > 500 procedures at risk at 3 years post-primary of which 5 were inferior by at least 20 % relative risk of which, one was inferior by at least 100 % relative risk. 14 constructs were identified with > 500 procedures at risk at 10 years with 5 inferior by at least 20 %, of which 2 were inferior by > 100 % relative risk. CONCLUSIONS: We discerned that there is great variability in construct performance and at all time points, greater than 25 % of constructs are inferior to the best performing construct by at least 20 %. These results can help inform patients, clinicians and health care funders when considering TKR surgery.

National prospective cohort study of the burden of acute small bowel obstruction.

Background: Small bowel obstruction is a common surgical emergency, and is associated with high levels of morbidity and mortality across the world. The literature provides little information on the conservatively managed group. The aim of this study was to describe the burden of small bowel obstruction in the UK. Methods: This prospective cohort study was conducted in 131 acute hospitals in the UK between January and April 2017, delivered by trainee research collaboratives. Adult patients with a diagnosis of mechanical small bowel obstruction were included. The primary outcome was in-hospital mortality. Secondary outcomes included complications, unplanned intensive care admission and readmission within 30 days of discharge. Practice measures, including use of radiological investigations, water soluble contrast, operative and nutritional interventions, were collected. Results: Of 2341 patients identified, 693 (29·6 per cent) underwent immediate surgery (within 24 h of admission), 500 (21·4 per cent) had delayed surgery after initial conservative management, and 1148 (49·0 per cent) were managed non-operatively. The mortality rate was 6·6 per cent (6·4 per cent for non-operative management, 6·8 per cent for immediate surgery, 6·8 per cent for delayed surgery; P = 0·911). The major complication rate was 14·4 per cent overall, affecting 19·0 per cent in the immediate surgery, 23·6 per cent in the delayed surgery and 7·7 per cent in the non-operative management groups (P < 0·001). Cox regression found hernia or malignant aetiology and malnutrition to be associated with higher rates of death. Malignant aetiology, operative intervention, acute kidney injury and malnutrition were associated with increased risk of major complication. Conclusion: Small bowel obstruction represents a significant healthcare burden. Patient-level factors such as timing of surgery, acute kidney injury and nutritional status are factors that might be modified to improve outcomes.

Breech presentation is associated with lower adolescent tibial bone strength.

We compared bone outcomes in adolescents with breech and cephalic presentation. Tibia bone mineral content, density, periosteal circumference, and cross-sectional moment of inertia were lower in breech presentation, and females with breech presentation had lower hip CSA. These findings suggest that prenatal loading may exert long-lasting influences on skeletal development. INTRODUCTION: Breech position during pregnancy is associated with reduced range of fetal movement, and with lower limb joint stresses. Breech presentation at birth is associated with lower neonatal bone mineral content (BMC) and area, but it is unknown whether these associations persist into later life. METHODS: We examined associations between presentation at onset of labor, and tibia and hip bone outcomes at age 17 years in 1971 participants (1062 females) from a UK prospective birth cohort that recruited > 15,000 pregnant women in 1991-1992. Cortical BMC, cross-sectional area (CSA) and bone mineral density (BMD), periosteal circumference, and cross-sectional moment of inertia (CSMI) were measured by peripheral quantitative computed tomography (pQCT) at 50% tibia length. Total hip BMC, bone area, BMD, and CSMI were measured by dual-energy X-ray absorptiometry (DXA). RESULTS: In models adjusted for sex, age, maternal education, smoking, parity, and age, singleton/multiple births, breech presentation (n = 102) was associated with lower tibial cortical BMC (- 0.14SD, 95% CI - 0.29 to 0.00), CSA (- 0.12SD, - 0.26 to 0.02), BMD (- 0.16SD, - 0.31 to - 0.01), periosteal circumference (- 0.14SD, - 0.27 to - 0.01), and CSMI (- 0.11SD, - 0.24 to 0.01). In females only, breech presentation was associated with lower hip CSA (- 0.24SD, - 0.43 to 0.00) but not with other hip outcomes. Additional adjustment for potential mediators (delivery method, birthweight, gestational age, childhood motor competence and adolescent height and body composition) did not substantially affect associations with either tibia or hip outcomes. CONCLUSIONS: These findings suggest that prenatal skeletal loading may exert long-lasting influences on skeletal size and strength but require replication.

Higher 30-day mortality associated with the use of intramedullary nails compared with sliding hip screws for the treatment of trochanteric hip fractures: a prospective national registry study.

AIMS: The aim of this study was to investigate the association between the type of operation used to treat a trochanteric fracture of the hip and 30-day mortality. PATIENTS AND METHODS: Data on 82 990 patients from the National Hip Fracture Database were analyzed using generalized linear models with incremental case-mix adjustment for patient, non-surgical and surgical characteristics, and socioeconomic factors. RESULTS: The use of short and long intramedullary nails was associated with an increase in 30-day mortality (adjusted odds ratio (OR) 1.125, 95% confidence interval (CI) 1.040 to 1.218; p = 0.004) compared with the use of sliding hip screws (12.5% increase). If this were causative, it would represent 98 excess deaths over the four-year period of the study and one excess death would be caused by treating 112 patients with an intramedullary nail rather than a sliding hip screw. CONCLUSION: There is a 12.5% increase in the risk of 30-day mortality associated with the use of an intramedullary nail compared with a sliding hip screw in the treatment of a trochanteric fractures of the hip.

Optimizing collaborator recruitment and maintaining engagement via social media during large multicentre studies: lessons learned from the National Audit of Small Bowel Obstruction (NASBO).

AIM: The National Audit of Small Bowel Obstruction was a UK-wide study active in early 2017. A Twitter© account was used to interact with collaborators and the public throughout the study to assess whether the use of social media improved study engagement and to establish which Tweet signature styles achieved the highest levels of reach and engagement. METHOD: Twitter© analytics for @NASBO2017 covering June 2016-May 2017 were reviewed. The number of impressions, Tweet engagements and the engagement rate were analysed according to study stage. RESULTS: A total of 176 Tweets were made over the study period. The median number of impressions achieved by a Tweet was 533 (75-2709). 3863 engagements were made with National Audit of Small Bowel Obstruction Tweets with a median number of 10 (0-159) per Tweet. The average overall Tweet engagement rate was 3.3% (0%-14.2%). Tweets with most impressions either used images or tagged institutions (e.g. Royal Colleges, professional bodies). The number of impressions and engagement with the Tweets increased over the study period, due to the incremental growth of the National Audit of Small Bowel Obstruction Twitter© account and the identification of successful Tweet styles. CONCLUSIONS: Social media provided a major contribution to a successful concerted policy of maintaining collaborator engagement during the National Audit of Small Bowel Obstruction. The use of images and videos and tagging of relevant professional bodies aided the reach and engagement of each Tweet. These data can be used to inform engagement strategies for future collaborative projects.

Current management of small bowel obstruction in the UK: results from the National Audit of Small Bowel Obstruction clinical practice survey.

AIM: Small bowel obstruction (SBO) is associated with high rates of morbidity and mortality. The National Audit of Small Bowel Obstruction (NASBO) is a collaboration between trainees and specialty associations to improve the care of patients with SBO through national clinical audit. The aim of this study was to define current consultant practice preferences in the management of SBO in the UK. METHOD: A survey was designed to assess practice preferences of consultant surgeons. The anonymous survey captured demographics, indications for surgery or conservative management, use of investigations including water-soluble contrast agents (WSCA), use of laparoscopy and nutritional support strategies. The questionnaire underwent two pilot rounds prior to dissemination via the NASBO network. RESULTS: A total of 384 responses were received from 131 NASBO participating units (overall response rate 29.2%). Abdominal CT and serum urea and electrolytes were considered essential initial investigations by more than 80% of consultants. Consensus was demonstrated on indications for early surgery and conservative management. Three hundred and thirty-eight (88%) respondents would consider use of WSCA; of these, 328 (97.1%) would use it in adhesive SBO. Two hundred (52.1%) consultants considered a laparoscopic approach when operating for SBO. Oral nutritional supplements were favoured in operatively managed patients by 259 (67.4%) respondents compared with conservatively managed patients (186 respondents, 48.4%). CONCLUSION: This survey demonstrates consensus on imaging requirements and indications for early surgery in the management of SBO. Significant variation exists around awareness of the need for nutritional support in patients with SBO, and on strategies to achieve this support.

Joint modelling compared with two stage methods for analysing longitudinal data and prospective outcomes: A simulation study of childhood growth and BP.

There is a growing debate with regards to the appropriate methods of analysis of growth trajectories and their association with prospective dependent outcomes. Using the example of childhood growth and adult BP, we conducted an extensive simulation study to explore four two-stage and two joint modelling methods, and compared their bias and coverage in estimation of the (unconditional) association between birth length and later BP, and the association between growth rate and later BP (conditional on birth length). We show that the two-stage method of using multilevel models to estimate growth parameters and relating these to outcome gives unbiased estimates of the conditional associations between growth and outcome. Using simulations, we demonstrate that the simple methods resulted in bias in the presence of measurement error, as did the two-stage multilevel method when looking at the total (unconditional) association of birth length with outcome. The two joint modelling methods gave unbiased results, but using the re-inflated residuals led to undercoverage of the confidence intervals. We conclude that either joint modelling or the simpler two-stage multilevel approach can be used to estimate conditional associations between growth and later outcomes, but that only joint modelling is unbiased with nominal coverage for unconditional associations.

Central sensitization as a determinant of patients' benefit from total hip and knee replacement.

BACKGROUND: Discrepancies exist between osteoarthritic joint changes and pain severity before and after total hip (THR) and knee (TKR) replacement. This study investigated whether the interaction between pre-operative widespread hyperalgesia and severity of radiographic osteoarthritis (OA) was associated with pain severity before and after joint replacement. METHODS: Data were analysed from 232 patients receiving THR and 241 receiving TKR. Pain was assessed pre-operatively and at 12 months post-operatively using the WOMAC Pain Scale. Widespread hyperalgesia was assessed through forearm pressure pain thresholds (PPTs). Radiographic OA was evaluated using the Kellgren and Lawrence scheme. Statistical analysis was conducted using multilevel models, and adjusted for confounding variables. RESULTS: Pre-operative: In knee patients, there was weak evidence that the effect of PPTs on pain severity was greater in patients with more severe OA (Grade 3 OA: ß = 0.96 vs. Grade 4: ß = 4.03), indicating that in these patients higher PPTs (less widespread hyperalgesia) was associated with less severe pain. In hip patients, the effect of PPTs on pain did not differ with radiographic OA (Grade 3 OA: ß = 3.95 vs. Grade 4: ß = 3.67). Post-operative: There was weak evidence that knee patients with less severe OA who had greater widespread hyperalgesia benefitted less from surgery (Grade 3 OA: ß = 2.28; 95% CI -1.69 to 6.25). Conversely, there was weak evidence that hip patients with more severe OA who had greater widespread hyperalgesia benefitted more from surgery (Grade 4 OA: ß = -2.92; 95% CI -6.58 to 0.74). CONCLUSIONS: Widespread sensitization may be a determinant of how much patients benefit from joint replacement, but the effect varies by joint and severity of structural joint changes. SIGNIFICANCE: Pre-operative widespread hyperalgesia and radiographic osteoarthritis (OA) severity may influence how much patients benefit from joint replacement. Patients undergoing knee replacement with less severe OA and greater widespread hyperalgesia benefitted less from surgery than patients with less hyperalgesia. Patients undergoing hip replacement with more severe OA and greater widespread hyperalgesia benefitted more than patients with less hyperalgesia.

Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis.

We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren-Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM-OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8years, 74% female) and 1937 control knees in 991 controls (63.4years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren-Lawrence grade≥2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p<0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.

Perineal hernia formation following extralevator abdominoperineal excision.

AIM: Extralevator abdominoperineal excision (ELAPE) has become increasingly used because of some evidence of improved oncological outcome. It is, however, thought to be associated with a higher incidence of perineal hernia formation, although the exact incidence is not known. The aim of this study was to identify the incidence of perineal hernia after ELAPE. METHOD: The case notes of patients over a 54-month period were reviewed. The perineal closure technique, perineal complications and management plan were recorded. RESULTS: During the study period, 56 patients underwent ELAPE, of whom 24 (44%) developed a perineal wound complication. Primary perineal closure was performed with (eight patients) and without (32 patients) insertion of a biological mesh or myocutaneous flap. Perineal hernia was the commonest complication (26%) and occurred in nine (45%) of 20 patients who had a laparoscopic ELAPE. CONCLUSION: Perineal hernia formation was the commonest perineal complication of ELAPE and occurred in nearly half of patients having a laparoscopic ELAPE.

Assessment of producers' response to Salmonella biosecurity issues and uptake of advice on laying hen farms in England and Wales.

High standards of biosecurity are known to reduce the risk of disease outbreaks; however, uptake of advice and implementation of biosecurity measures are dependent on many factors. This study assessed the uptake of targeted biosecurity advice by 60 laying hen farms provided during biosecurity audit visits. Advice was provided as bullet point cards focusing on specific areas identified as benefitting from improvement. These covered site entrance, site tidiness, vaccination, boot hygiene, hand hygiene, house tidiness, rodent control, fly control, red mite control and cleaning and disinfection between flocks. Background knowledge of Salmonella and biosecurity and farmers' willingness and intent to implement additional measures were assessed. About 50% of the principal decision-makers had basic background knowledge of Salmonella, with 22% considered well informed; almost all agreed that biosecurity could impact on Salmonella control and many appeared willing to implement additional biosecurity measures. Sixty-three per cent of study farms were categorised using the Defra Farmer Segmentation Model as Modern Family Businesses (MFBs), with 7-11% of farms being categorised as Custodian, Lifestyle Choice, Pragmatist or Challenged Enterprise; however, categorisation, did not determine uptake of advice. The most frequently used advice cards were boot hygiene, red mite control, hand hygiene, site entrance and cleaning and disinfection; uptake of advice ranged from 54 to 80% depending on the advice card. Uptake of advice by the farmers was encouraging, especially considering it was being provided by people other than their usual source of biosecurity information. Those who did not implement the recommended measures cited cost, difficulty of enforcement and practicality as the main reasons. However, the positive uptake of advice and implementation of recommended measures by many farmers demonstrates that targeted advice, discussed face to face with farmers, on a small number of key areas, is a potentially effective method of providing biosecurity information to complement more lengthy formal advisory reports.

Distinct relationships of intramuscular and subcutaneous fat with cortical bone: findings from a cross-sectional study of young adult males and females.

CONTEXT: Intracellular fat within muscle and visceral tissue has been suggested to adversely influence bone development. OBJECTIVE: The aim of the study was to evaluate associations between im fat, as reflected by muscle density as measured by peripheral quantitative computed tomography, and cortical bone parameters in young adults. DESIGN/SETTING/PARTICIPANTS: We conducted a cross-sectional analysis of 1703 males and 2243 females aged 17.8 years from the Avon Longitudinal Study of Parents and Children. OUTCOME MEASURES: We measured cortical bone parameters from midtibial peripheral quantitative computed tomography scans. RESULTS: Muscle density (inversely related to im fat) was inversely associated with periosteal circumference (PC) (beta = -0.07 [95% confidence interval (CI), -0.1, -0.04]), cortical bone mineral density (BMDC) (beta = -0.21 [95% CI, -0.26, -0.17]), and cortical thickness (CT) (beta = -0.37 [95% CI, -0.42, -0.33]) (males and females combined, adjusted for age, height, gender, and muscle cross-sectional area). In contrast, sc fat area was positively associated with PC (beta = 0.10 [95% CI, 0.07, 0.12]), but no association was seen with BMDC or CT. To examine the role of candidate intermediary metabolic pathways, analyses were repeated after adjustment for insulin, C-reactive protein, and ß-C-telopeptides of type I collagen. Whereas similar associations were observed after adjustment for insulin and C-reactive protein, the association between muscle density and BMDC was partially attenuated by adjustment for ß-C-telopeptides of type I collagen (beta = -0.14 [95% CI, -0.20, -0.08]). CONCLUSION: Although im and sc fat were both positively associated with cortical bone mass, the nature of these relationships differed in that im fat was predominantly associated with CT and BMDC, whereas sc fat was mainly associated with PC. These relationships were largely independent of candidate metabolic pathways, such as altered bone resorption, insulin resistance, or inflammation.

Tuberculin manufacturing source and breakdown incidence rate of bovine tuberculosis in British cattle, 2005-2009.

The single intradermal comparative cervical tuberculin (SICCT) test is the primary test used for surveillance for bovine tuberculosis (bTB) in cattle in Great Britain (GB). The tuberculin used can, with other factors, influence test accuracy. In this analysis, the detection of infected cattle in GB 2005-2009 was compared between SICCT tests using tuberculins manufacturered by different manufacturers. Higher rates of reactors (adjusted rate 209 vs 186 per 100,000 tests, P = 0.003) and herd bTB incidents (adjusted total breakdown rate 5.1 vs 4.5 per 100 herd-years at risk, P < 0.001) were detected using tuberculin manufactured at Weybridge compared with Lelystad. However, confirmation of infection in reactors by postmortem evidence was higher with Lelystad tuberculin (adjusted percent 44.1 vs 47.1, P = 0.018). The findings, overall, suggest slightly higher test sensitivity and lower test specificity associated with Weybridge tuberculin compared with Lelystad. Assuming effective adjustment for confounding, the overall impact of tuberculin manufacturing source (2007-2009), was calculated to range somewhere between 315 false positive breakdowns, and 1086 bTB breakdowns missed (624 confirmed) as a result of using Weybridge and Lelystad tuberculin, respectively. However, animals that tested negative to the SICCT were not slaughtered at the time of the tests, so definitive conclusions are not possible.

Quantitative profiling of PrP(Sc) peptides by high-performance liquid chromatography mass spectrometry to investigate the diversity of prions.

Prions are proteins that can exist in two (or more) folding states, a normal or cellular form and a series of infectious or prion forms, which are prone to aggregate. The prion form can induce conversion of the cellular form and so transmit phenotypic effects of this structural rearrangement within and between cells and organisms. The conversion of PrP(C), the mammalian prion glycoprotein, to its prion form, PrP(Sc), in the brain is a precursor to progressive neurological degeneration, and the various folded forms of PrP(Sc) (defined by the size and glycosylation of protease-resistant core peptides of the PrP aggregates, PrP(res)) are characteristic of a particular neurodegenerative phenotype or prion disease. Here, quantitative multiplex mass spectrometry was used for N-terminal amino acid profiling (N-TAAP) of PrP(res) from sheep affected by scrapie, the prion disease of small ruminants, to rapidly assess the diversity of prions within particular flocks. In 29 cases, PrP(res) concentrations varied from below the limit of detection (350 fmol/g) to 15 pmol/g wet brain. Although most had a single N-TAAP profile, two novel variants were identified: one common to the ARH/ARQ animals in this study and one in an animal of the wild-type sheep PrP genotype (ARQ/ARQ).

Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle - an update.

BACKGROUND: To provide information on dose-response and aid in modelling the exposure dynamics of the BSE epidemic in the United Kingdom groups of cattle were exposed orally to a range of different doses of brainstem homogenate of known infectious titre from clinical cases of classical bovine spongiform encephalopathy (BSE). Interim data from this study was published in 2007. This communication documents additional BSE cases, which occurred subsequently, examines possible influence of the bovine prion protein gene on disease incidence and revises estimates of effective oral exposure. FINDINGS: Following interim published results, two further cattle, one dosed with 100 mg and culled at 127 months post exposure and the other dosed with 10 mg and culled at 110 months post exposure, developed BSE. Both had a similar pathological phenotype to previous cases. Based on attack rate and incubation period distribution according to dose, the dose estimate at which 50% of confirmed cases would be clinically affected was revised to 0.15 g of the brain homogenate used in the experiment, with a 95% confidence interval of 0.03-0.79 g. Neither the full open reading frame nor the promoter region of the prion protein gene of dosed cattle appeared to influence susceptibility to BSE, but this may be due to the sample size. CONCLUSIONS: Oral exposure of cattle to a large range of doses of a BSE brainstem homogenate produced disease in all dose groups. The pathological presentation resembled natural disease. The attack rate and incubation period were dependent on the dose.