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A case study of organizational transformation is used to illustrate how concepts from knowledge generation can be used to reframe some of the typical issues that arise, and make suggestions for practice. For organizational transformation to occur, an organization's members need to evolve new tacit knowledge about the way they interact with each other and external stakeholders, and how they coordinate their activities.

Vaccination of chickens against avian coccidiosis in chickens often involves storing Eimeria oocysts for months after oocyst propagation and sporulation. The purpose of this study was to determine how long E. acervulina, E. maxima , and E. tenella oocysts remained viable when stored at refrigeration (4°C) or egg room (20°C) temperatures. Separate tubes containing E. acervulina, E. maxima , or E. tenella oocysts were stored at these temperatures and a sample removed every 3 mo for inoculating chickens for evidence of a patent infection. Also, an aliquot of each Eimeria species at each time–temperature combination was subjected to in vitro excystation to quantify the relative number of released sporozoites to intact (nonexcysted) sporocysts. Eimeria tenella appeared to be most susceptible to storage in that no oocyst production was observed at 9 mo at either temperature. Although E. maxima oocysts were viable at 9 mo, no oocyst production was observed at 12 mo storage at these 2 temperatures. Quite unexpected was that E. acervulina was much more stable than E. tenella and E. maxima remaining viable up to and including 27 mo at 4°C and up to and including 12 mo at 20°C. No consistent correlation was observed between in vivo oocyst production and in vitro excystation arising from these 2 respective temperatures (E. acervulina r = 0.58, r = 0.54; E. maxima r = 0.90, r = 0.54; E. tenella r = 0.38, r = 0.90). These data indicate that attention must be paid to time and temperature of Eimeria oocyst storage, and that sporozoite excystation may not be a good indicator of oocyst viability, particularly at later timepoints in incubation. [ABSTRACT FROM AUTHOR]

Highlights • Cryptosporidium spp. CP15 and CSL peptides stimulate antibody production. • Antibodies induced by CP15-1 and CP15-3 peptides neutralise parasite entry in vitro. • CP15 plays an important role in sporozoite entry to enterocytes. • A multiple-epitope vaccine is required for complete entry blocking. Abstract Cryptosporidium spp. is a zoonotic intracellular protozoan and a significant cause of diarrhoea in humans and animals worldwide. This parasite can cause high morbidity in immunocompromised people and children in developing countries, livestock being the main reservoir. This study was aimed at performing preliminary tests on Swiss albino weaned mice (ICR) to evaluate the humoral immune response induced against peptides derived from Cryptosporidium parvum CP15 (15 kDa sporozoite surface antigen) and CSL (circumsporozoite-like antigen) proteins. Peptides were identified and characterised using bioinformatics tools and were chemically synthesised. The antibody response was determined and the neutralising effect of antibodies was measured in cell culture. Despite all peptides studied here were capable of stimulating antibody production, neutralising antibodies were detected for just two of the CP15-derived ones. Additional studies aimed at evaluating further the potential of such peptides as vaccine candidates are thus recommended. [ABSTRACT FROM AUTHOR]

Eimeria maxima is one of the most pathogenic species of avian coccidia, yet it is unknown why different E. maxima strains differ in the pathogenic effects they cause in chickens. The purpose of this study was to determine if a more pathogenic E. maxima strain (APU1) was also more fecund than a less pathogenic E. maxima strain (APU2). At identical doses, E. maxima APU1 always produces greater intestinal lesions and lower weight gain compared to E. maxima APU2. Using a dose response study, median and mean intestinal lesion scores in E. maxima APU1-infected chickens were greater by a score of 1–1.5 compared to chickens infected with E. maxima APU2. Likewise, weight gain depression in E. maxima APU1-infected chickens was 20–25% greater (equivalent to 110–130 g body weight) than in E. maxima APU2-infected chickens. In order to understand the underlying cause of these observed clinical effects, 120 broiler chicks (5 oocyst levels, 6 replicates/level) were inoculated with various doses of E. maxima APU1 or APU2 oocysts. The dynamics of oocyst shedding was investigated by collecting fecal material every 12 h from 114 to 210 h post-inoculation (p.i.) and every 24 h thereafter from 210 to 306 h, and then processed for measuring E. maxima oocyst output. Oocysts were first observed at 138 h p.i., and time of peak oocyst production was nearly identical for both E. maxima APU1 and APU2 around 150–162 h. Total oocyst production was 1.1–2.6 fold higher at all dose levels for E. maxima APU1 compared to E. maxima APU2, being significantly higher (P < 0.05) at the log 1.5 dose level. Other groups of chickens were infected with higher doses of E. maxima APU1 or APU2 oocysts, and intestinal lesions were assessed by histology at 72, 96, 120, and 144 h p.i. Although schizonts, gamonts, and oocysts were observed at expected time-points, no obvious differences were noted in lesions induced by the two E. maxima strains. This study showed that the greater fecundity of E. maxima APU1 compared to E. maxima APU2 explains in part the observed differences in pathogenicity of the two E. maxima strains, but that other factors may contribute to differences in observed clinical effects. [ABSTRACT FROM AUTHOR]

To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis. A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938). There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702–0.724) in the internal test and 0.744 (95% CI, 0.741–0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673–0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33–3.87, P =.004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07–5.20, P =.03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs. QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival. [Display omitted] We demonstrate that quantitative analysis of digitized images of colorectal carcinoma can improve prediction of tumor recurrence and place tumors into clinically relevant prognostic risk groups. [ABSTRACT FROM AUTHOR]

Study objective: We test the hypothesis that anesthesia, measured as pain scores, induced by a novel topical anesthetic putty is non-inferior (margin=1.3) to that provided by conventional lidocaine infiltration for the repair of lacerations. Methods: A randomized controlled trial was conducted in the emergency department (ED) of a local hospital. Participants were randomly allocated to receive either infiltration anesthesia or topical anesthetic putty as per the trial protocol. Pain scores were recorded 15 minutes after infiltration and 30 minutes after topical anesthetic putty application. Median pain scores were compared between groups. Wound evaluation scores were conducted after 7 to 10 days and adverse events were monitored for both groups of participants throughout the study. Results: One hundred and ten participants were enrolled in the study, with 56 receiving infiltration and 54 receiving topical anesthetic putty. The median difference between the pain scores of the 2 groups was 0 (95% confidence interval –1 to 0). There were no substantial differences between the 2 groups in terms of either the wound evaluation scores or the incidence of adverse events. Conclusion: The novel topical anesthetic putty was not inferior to infiltration with lidocaine with respect to the pain experienced during suturing, and this putty is a feasible alternative to infiltration anesthesia of lacerations in the ED. [Copyright &y& Elsevier]

Abstract: Background: Sudden cardiac death is the leading cause of death among firefighters in the United States. Fire departments commonly maintain physical examination protocols, often with exercise stress testing, to detect risk of coronary heart disease. Objective: We sought to determine whether coronary calcium detected by electron beam computed tomography (EBCT) adds incremental risk stratification beyond the traditional risk factors in asymptomatic community-based firefighters. Methods: Three hundred ninety nine asymptomatic firefighters underwent a coronary calcium scan on a GE/Imatron C-150 Ultrafast EBCT scanner, using standardized imaging protocols. Framingham risk factor data were obtained on each patient by using a questionnaire. Agatston scores were derived and compared with national database of Agatston scores for asymptomatic populations on the basis of age and sex, allowing determination of a calcium percentile for each score. Results: Coronary calcium was found only in men >34 years of age. Of the 53% who had positive scans (Agatston score > 0), 87% had higher than average Agatston scores compared with a national database (P < 0.01). Agatston score above the 75th percentile was found in 57% of firefighters. No correlation was observed between traditional risk factors and those with and without coronary calcium. Conclusions: Firefighters have a high burden of calcified coronary atherosclerosis, greater than anticipated on the basis of age and coronary risk factors. [Copyright &y& Elsevier]

Background & Aims: The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene. Methods: A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification. Results: Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5–132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P = .01), had a higher proportion of right-sided (P = .01), synchronous cancers (P < .01), and personal history of adenomatous polyps (P = .003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02–2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P = .02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction < .001). Conclusions: Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways. [Copyright &y& Elsevier]

Abstract: Background: There are currently a number of different methods available to obtain anaesthesia in minor dermatological procedures. Although intradermal infiltration of 1% lidocaine is the favoured method for anaesthesia induction in laceration repair, it can cause significant pain in itself. Topical anaesthesia has been investigated as an alternative to infiltration anaesthesia, with the majority of studies looking at preparations of either TAC (tetracaine, adrenaline and cocaine) or LAT (lidocaine, adrenaline and tetracaine). Methods: A computerised search of the literature was undertaken, using Medline, Cinahl and the Cochrane Library, to identify studies of interest to this review. Reference lists were examined for further relevant papers. Aims: This paper aims to provide an overview of the use of topical anaesthetics, in laceration repair, in Emergency Medicine (EM) departments. Conclusion: The literature has shown that the induction of anaesthesia in lacerations has remained largely unchanged over the past few years, with lidocaine infiltration still the preferred method. Many reasons have been put forward as to why topical anaesthetics are not commonly used in the UK. Perhaps it would be beneficial to carry out work in relation to alternative formulations as opposed to overcoming the difficulties associated with formulations that are already available. [Copyright &y& Elsevier]

Background & Aims: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%–20% for colorectal cancer, 15% for endometrial cancer, and 25%–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. [Copyright &y& Elsevier]

The prevalence, size, genome, and life cycle of Eimeria acervulina make this organism a good surrogate for Cyclospora cayetanensis, a protozoan that causes gastroenteritis in humans, including recent outbreaks in the United States and Canada associated with contaminated raspberries and basil. Laboratory studies of C. cayetanensis are difficult because of the lack of readily available oocysts and of infection models and assays. UV radiation and high-hydrostatic-pressure processing (HPP) are both sale technologies with potential for use on fresh produce. Raspberries and basil were inoculated with sporulated E. acervulina oocysts at high (106 oocysts) and low (104 oocysts) levels, and inoculated and control produce were treated with UV (up to 261 mW/cm²) or HPP (550 MPa at 40°C for 2 min). Oocysts recovered from produce were fed to 3-week-old broiler chickens, which were scored for weight gain, oocyst shedding, and lesions at 6 days postinoculation. Oocysts exhibited enhanced excystation on raspberries but not on basil. Birds fed oocysts from UV-treated raspberries had reduced infection rates, which varied with oocyst inoculum level and UV intensity. Birds fed oocysts from UV-treated raspberries (104 oocysts) were asymptomatic but shed oocysts, and birds fed oocysts from UV-treated basil (104 oocysts) were asymptomatic and did not shed oocysts. Birds fed oocysts from HPP-treated raspberries and basil were asymptomatic and did not shed oocysts. These results suggest that UV radiation and HPP may be used to reduce the risk for cyclosporiasis infection associated with produce. Both treatments yielded healthy animals; however, HPP was more effective, as indicated by results for produce with higher contamination levels. [ABSTRACT FROM AUTHOR]

Background: The literature regarding the association between breast-feeding and atopic diseases has been contradictory. Objective: We have assessed the relationship between breast-feeding and atopic disorders in a cohort followed into middle age. Methods: The Tasmanian Asthma Study is a population-based prospective cohort study that has followed participants from the age of 7 to 44 years. Exclusive breast-feeding in the first 3 months of life was examined as a risk factor for atopic diseases by using multiple logistic regression and generalized estimating equation analyses. Results: At age 7 years, exclusively breast-fed children with a maternal history of atopy had a marginally lesser risk of current asthma than those not exclusively breast-fed (odds ratio [OR], 0.8; 95% CI, 0.6-1.0). However, after age 7 years, the risk reversed, and exclusively breast-fed children had an increased risk of current asthma at 14 (OR, 1.46; 95% CI, 1.02-2.07), 32 (OR, 1.84; 95% CI, 1.06-3.3), and 44 (OR, 1.57; 95% CI, 1.15-2.14) years. Exclusively breast-fed children also had a reduced risk of food allergy at age 7 years but an increased risk of food allergy (OR, 1.26; 95% CI, 1.1-1.5) and allergic rhinitis (OR, 1.2; 95% CI, 1.0-1.3) at 44 years. Conclusion: Exclusively breast-fed babies with a maternal history of atopy were less likely to develop asthma before the age of 7 years, but more likely to develop asthma after the age of 7 years. Clinical implications: The current recommendation to breast-feed high-risk infants for protection against early wheezing illness can be confirmed. However, the recommendation should be reconsidered for protection against allergic asthma and atopy in the longer term. [Copyright &y& Elsevier]

Background: The association between allergic rhinitis and asthma is well documented, but the temporal sequence of this association has not been closely examined. Objective: We sought to assess the associations between childhood allergic rhinitis and (1) asthma incidence from preadolescence to middle age and (2) asthma persistence to middle age. Methods: Data were gathered from the 1968, 1974, and 2004 surveys of the Tasmanian Asthma Study. Cox regression was used to examine the association between childhood allergic rhinitis and asthma incidence in preadolescence, adolescence, and adult life. Binomial regression was used to examine the association between childhood allergic rhinitis and asthma beginning before the age of 7 years and persisting at age 44 years. Results: Childhood allergic rhinitis was associated with a significant 2- to 7-fold increased risk of incident asthma in preadolescence, adolescence, or adult life. Childhood allergic rhinitis was associated with a 3-fold increased risk of childhood asthma persisting compared with remitting by middle age. Conclusions: Childhood allergic rhinitis increased the likelihood of new-onset asthma after childhood and the likelihood of having persisting asthma from childhood into middle age. Clinical implications: Asthma burden in later life might be reduced by more aggressive treatment of allergic rhinitis in early life. [Copyright &y& Elsevier]

Background & Aims: The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H). Methods: Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H. Results: Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval [CI], 5.9–14.1), proximal subsite (OR, 4.7; 95% CI, 3.1–7.3), mucinous histology (OR, 2.8; 95% CI, 1.7–4.8), poor differentiation (OR, 1.9; 95% CI, 1.2–3.1), Crohn’s-like reaction (OR, 1.9; 95% CI, 1.2–2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3–2.9). MsPath score ≥1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H. Conclusions: The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score <1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years. [Copyright &y& Elsevier]

Background & Aims: Cancer risks for mismatch repair gene mutation carriers have been derived almost exclusively using families ascertained owing to their strong cancer family history. These may be overestimates, due to analytic problems, and not generalizable. We estimated average cancer risks for mutations identified in population-based early onset colorectal cancer cases (probands) unselected for family history. Methods: Data were cancer histories and mutation status (carrier, non-carrier, or unknown) of 17 mismatch repair gene mutation carrier probands with colorectal cancer diagnosed before age 45 (8 hMLH1, 4 hMSH2, 4 hMSH6, 1 hPMS2) and their first- and second-degree relatives. We used modified segregation analysis theory, adjusting for the family being ascertained through the proband being an early onset mutation carrier. Results: Eleven carrier probands (64%) were from families meeting the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. The cumulative risk for colorectal cancer (95% confidence interval) to age 70 was 45% (29%–62%) for men and 38% (19%–51%) for women. Corresponding risks were 67% (47%–84%) and 72% (48%–85%) for any hereditary nonpolyposis colorectal cancer–related cancer. Compared with the general population, colorectal cancer incidence for men was approximately 180-fold higher before age 50, but about the same after age 50. For women, incidence was approximately 100-fold higher before age 50 and 7-fold higher thereafter. Conclusions: For carriers of the mutations in the mismatch repair genes that cause early onset colorectal cancer, colorectal cancer increases rapidly until age 50, and the incidence decreases to general population levels at older ages. [Copyright &y& Elsevier]

Abstract: Objective: Familial aggregation, a primary theme in genetic epidemiology, can be estimated from family studies based on an index person. The excess risk due to the presence of affected family members can be classified according to whether disease in the relatives is considered a risk factor for the index person (type I relative risk) or whether the disease status of the index person is considered a risk factor for the relatives (type II relative risk). Study Design and Setting: A meta-analysis of published colorectal cancer studies reporting a measure of familial association was performed and application of multilevel linear regression to model age-specific relative risks presented. Results: The pooled type I relative risk of colorectal cancer given any affected first-degree relative (based on 20 studies) was 2.26 (95% confidence interval CI = 1.86, 2.73) and decreased with the age of the consultand. The pooled type II estimate (based on seven studies) was 2.81 (95% CI = 2.05, 3.85). Conclusion: Type I relative risks are useful in clinical counseling settings when a consultand wants to know his/her disease risk given his or her family history. Type II relative risks can be used to quantify the risk of disease to relatives of an affected individual and then identify subjects eligible for screening. [Copyright &y& Elsevier]

Background & Aims: Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members. Methods: A subset of tumors from a total of 55 collected (25 polyps and 30 cancers) from 43 individuals across 11 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island. Results: All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of 19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of 12 stable MSI), a significant increase over HNPCC (0 of 15 or 0%), and unselected CRC (30 of 197 or 15.2%) (P < .05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs (P < .05). Conclusion: These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development. [Copyright &y& Elsevier]