Investigating the effect of prophylactic claw trimming on the interval between calving and first observed elevated locomotion score in pasture-based dairy cows.

AIMS: To evaluate, in a pasture-based dairy herd, the response to a three-time point hoof trimming regime on lameness incidence and time from calving to observation of an elevated locomotion score (LS). METHODS: This study was conducted on a 940-cow spring-calving herd in New Zealand's North Island between May 2018 and May 2019. Cows (n = 250) were randomly allocated to the hoof trimming group, with the remainder assigned to the non-trim cohort. One trained professional hoof trimmer used the five-step Dutch method to trim the hind feet of the trimming group. Throughout the subsequent production season, the whole herd was locomotion-scored fortnightly using the 4-point (0-3) Dairy NZ lameness score. Kaplan-Meier survival curves were used to assess the univariable effect of trimming on the interval between calving and first LS of ≥ 2 and first LS ≥ 1. A multivariable Cox proportional hazards regression was used to further evaluate the effect of trimming on time to elevated LS. RESULTS: Mean lameness (LS ≥ 2) prevalence was 2.6%, with 30% of cows having ≥ 4 observations during the study period when at least one LS was ≥ 2. For LS ≥ 1, mean prevalence was 40%, with 98.6% of cows having ≥ 4 observations during the study period when at least one LS was ≥ 1 during lactation. Hoof trimming had no apparent effect on the incidence of clinical lameness (LS ≥ 2) (trimmed vs. non-trimmed: 33.2% vs. 28.8%, respectively), but for LS ≥ 1, there was a small decrease in the incidence of LS ≥ 1 (trimmed vs. non-trimmed: 96.9% vs. 99.3%, respectively). The hazard of a cow having a first observed LS ≥ 2 in the control group was 0.87 (95% CI = 0.66-1.14) times that of the trimmed group; however, the hazard of a cow having a first LS ≥ 1 was 1.60 (95% CI = 1.37-1.88) times higher in the control than in the trimmed group. CONCLUSION AND CLINICAL RELEVANCE: On this farm, prophylactic hoof trimming had no clinically relevant impact on the incidence of clinical lameness and was not associated with clinically beneficial reductions in time to first observed LS ≥ 2. This may be because claw horn imbalance was not pronounced on this farm, with 53% of cows needing no trim on either hind limb on the first trimming occasion. Further research on the response to prophylactic trimming in pasture-based dairy cattle is required.

Blazing pathways through genetic mountains.

It is now widely accepted that high-throughput data sources will shed essential understanding on the inner workings of cellular and organism function. One key challenge is to distill the results of such experiments into an interpretable computational form that will be the basis of a predictive model. A predictive model represents the gold standard in understanding a biological system and will permit us to investigate the underlying cause of diseases and help us to develop therapeutics. Here I explore how discoveries can be based on high-throughput data sources and discuss how independent discoveries can be assembled into a comprehensive picture of cellular function.

Insulin binding and degradation by muscles from streptozotocin-diabetic rats.

Insulin degradtion by muscle was examined in normal, streptozotocin-induced diabetic rats, and diabetic rats treated with insulin. Insulin degradation by the 100,000 X g supernatant fractions was identical in all three groups, but insulin metabolism by the intact epitrochlaris muscle was significantly increased in diabetic animals. Insulin treatment of the diabetic animals partially restored the activity toward normal. Specific binding of 125l-insulin to the intact muscles was also increased in the diabetic animals. Streptozotocin diabetes, therefore, increased the binding and degradation of insulin by intact muscle but did not alter the insulin degradation by the total soluble intracellular degradative activity.

Amino Acid Utilization in Seeds of Loblolly Pine during Germination and Early Seedling Growth (I. Arginine and Arginase Activity).

The mobilization and utilization of the major storage proteins in loblolly pine (Pinus taeda L.) seeds following imbibition were investigated. Most of the seed protein reserves were contained within the megagametophyte. Breakdown of these proteins occurred primarily following radicle emergence and correlated with a substantial increase in the free amino acid pool in the seedling; the majority of this increase appeared to be the result of export from the megagametophyte. The megagametophyte was able to break down storage proteins and export free amino acids in the absence of the seedling. Arginine (Arg) was the most abundant amino acid among the principal storage proteins of the megagametophyte and was a major component of the free amino acid pools in both the seedling and the megagametophyte. The increase in free Arg coincided with a marked increase in arginase activity, mainly localized within the cotyledons and epicotyl of the seedling. Arginase activity was negligible in isolated seedlings. Experiments with phenylphosphorodiamidate, a urease inhibitor, supported the hypothesis that arginase participates in Arg metabolism in the seedling. The results of this study indicate that Arg could play an important role in the nutrition of loblolly pine during early seedling growth.

Purification and Characterization of Catalase from Loblolly Pine (Pinus taeda L.) Megagametophytes.

Catalase (EC 1.11.1.6) was purified to near homogeneity from isolated megagametophytes of germinated loblolly pine (Pinus taeda L.) seeds, and monospecific antibodies were elicited in rabbits. Following a procedure that involved acetone extraction, (NH4)2SO4 fractionation, and four chromatographic steps (i.e. DE-52 cellulose, Superdex-200, hydroxylapatite, and phenyl-Sepharose CL-4B), catalase was purified about 140-fold to a final specific activity of 2215 mmol min-1 mg-1 of protein. Cotton isocitrate lyase antibodies were used, and protein immunoblots revealed that the resolution on hydroxylapatite and phenyl-Sepharose allowed for the complete separation of catalase from contaminating isocitrate lyase. The molecular masses of the native enzyme and its subunit are 235 and 59 kD, respectively, indicating that the pine holoenzyme is a homotetramer. Loblolly pine catalase exists as multiple isoforms. When megagametophytes taken 7 d after imbibition at 30[deg]C were extracted, subjected to nondenaturing isoelectric focusing, and stained for catalase activity, at least four catalase isoforms were observed, including one dominant form with an isoelectric point of 6.87. Purified pine catalase is not a glycoprotein and has a ratio of absorbance at 208 nm to absorbance at 405 nm of 1.5. When probed with loblolly pine catalase antibodies, protein blots of cell-free extracts from megagametophytes of mature, stratified, and germinated loblolly pine seeds, the megagametophyte glyoxysomal fraction, and purified loblolly pine catalase all revealed one immunoreactive 59-kD polypeptide. This indicates that no detectable change in the enzyme's monomeric molecular mass occurs during seed stratification and germination, early seedling growth, and purification.

Systematic review of clinical prediction rules for neuroimaging in the evaluation of dementia.

BACKGROUND: Clinical practice guidelines for dementia do not recommend routine neuroimaging but vary in their recommended clinical prediction rules to identify patients who should undergo neuroimaging for potentially reversible causes of dementia. METHODS: Using a MEDLINE search supplemented by other strategies, we identified studies from January 1, 1983, through December 31, 1998, that evaluated the diagnostic performance of a clinical prediction rule. We calculated the sensitivity and specificity of each rule, then evaluated their diagnostic performance in a hypothetical cohort of 1000 patients with dementia, varying the prevalence of potentially reversible dementia from 1% to 15%. RESULTS: We identified 7 studies that evaluated at least 1 of 6 different clinical prediction rules. Only one rule consistently had high sensitivity (>85%) across all studies; none consistently had high specificity (>85%). Six of the 7 studies included less than 15 cases of potentially reversible dementia; thus the sensitivity and specificity for each rule had relatively wide confidence intervals. At a 5% prevalence of potentially reversible dementia, all rules had low positive predictive value (<15%) in our hypothetical cohort. Depending on the rule, our analysis predicts 6 to 44 of the 50 patients with potentially reversible dementia (5% prevalence in cohort of 1000 patients) would not undergo imaging. CONCLUSIONS: There is considerable uncertainty in the evidence underlying clinical prediction rules to identify which patients with dementia should undergo neuroimaging. Application of these rules may miss patients with potentially reversible causes of dementia.

Cardiomyopathy associated with the acquired immune deficiency syndrome.

Three cases of congestive cardiomyopathy complicating the acquired immune deficiency syndrome (AIDS) are reported. In one case, acute cardiac decompensation resulted in prolonged but ultimately reversible cardiogenic shock. In the second case, clinical signs of cardiac disease were precipitated by acute renal failure and fluid overload. In the third, congestive heart failure developed spontaneously and responded promptly to administration of diuretics but the patient died suddenly, apparently due to an arrhythmia. The etiology of cardiomyopathy in AIDS is unclear and the manifestations of cardiomyopathy in this setting range from subclinical to life threatening.

Tacrine use in nursing homes: implications for prescribing new cholinesterase inhibitors. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology.

OBJECTIVE: To describe the use of tacrine in nursing home residents using data from a clinically based resident assessment instrument used by all US nursing homes. METHODS: Data were from the Systematic Assessment of Geriatric Drug Use via Epidemiology (SAGE) database, a population-based data set with information on 329,520 patients admitted to all Medicare/Medicaid certified nursing homes in four US states (Maine, Mississippi, New York, and South Dakota) from 1992 through 1995. The SAGE database combines information from the Minimum Data Set (MDS) and the On-Line Survey and Certification Automated Record. We identified all residents receiving tacrine and up to five control residents per case matched on state, date of tacrine use, cognitive function, and dementia diagnosis. RESULTS: A total of 1,640 (0.5%) nursing home residents received tacrine at least once. Only 38% of these residents had a diagnosis of AD documented on the MDS; regardless of dementia diagnosis, 25% had severe cognitive impairment, 35% were severely dependent in activities of daily living (ADL), and 17% had both severe cognitive and ADL impairment. Only 8% achieved a therapeutic dose of at least 120 mg/d. After adjusting for confounding variables, wandering and being physically abusive were the strongest predictors of tacrine use. CONCLUSIONS: A minority of nursing home residents received tacrine. Of those who did, a significant proportion were unlikely to benefit from its use because of their level of cognitive and ADL impairment, or because low doses were used. As new medications become available for dementia, MDS data can be used by nursing homes to monitor the use of these therapies.

Practice styles of US compared to UK neurologists.

OBJECTIVE: This study assessed variation between neurologists in the United States and United Kingdom in their diagnostic and treatment decisions for commonly encountered neurologic presentations, and identified explanatory factors for any observed variation. METHODS: All 210 consultant neurologists in the United Kingdom and a nationally representative sample of 595 US neurologists received mailed surveys containing three detailed clinical scenarios depicting patients with (1) a single unprovoked seizure occurring 3 days previously, (2) early Parkinson's disease, and (3) dementia. The main study outcome measures were self-reported decisions regarding diagnostic test ordering and treatment, which were assessed after each scenario. Neurologists' practice characteristics, certainty about the diagnosis, and attitudes toward uncertainty were also measured. Survey response rates were 92% of US and 63% of UK neurologists. RESULTS: A higher proportion of US than UK neurologists indicated they would order additional diagnostic tests for all three scenarios (all p < 0.05); 77% of UK compared with 26% of US neurologists would manage a single unprovoked seizure without antiepileptic medication (p < 0.0001), but treatment of early Parkinson's disease was not different. Nearly all US and UK neurologists would obtain a neuroimaging study in the evaluation of dementia. International differences persisted after adjustment for differences in demographic and practice characteristics and for attitudes toward test use and clinical uncertainty. CONCLUSIONS: We identified large international variation in clinical decisions across three common neurologic conditions. Cross-country collaboration should explore these differences to develop consensus on standards of care.

Evidence of gonadal steroid-independent changes in activity of the central LH-releasing hormone pulse generator in developing bull calves.

To ascertain whether temporal changes in activity of the hypothalamo-pituitary axis in prepubertal bulls may occur independently of shifts in sensitivity to steroid feedback, the acute post-castration rise in serum gonadotrophins was monitored in bull calves castrated at monthly intervals from 4 to 9 months of age. Since a major feature of the gonadotrophin profiles of developing bulls is a change in LH pulse frequency early in life, pulsatile LH secretion after castration was used as an index of activity of the central LH-releasing hormone (LHRH) pulse generator. Relative to the day of castration (day 0) bull calves (n = 4) were bled at 20-min intervals for 8 h on day -3 and at 10-min intervals for 4 h on days 3, 5 and 7. During the first week after castration, 4-month-old bulls showed a higher (P less than 0.05) frequency of LH pulses compared with bulls at 8 and 9 months (1.13, 0.88 and 0.75 pulses/h respectively; pooled S.E.M. = 0.13). Mean LH levels before castration were higher (P less than 0.05) in 4-month-old bulls than in bulls at 7, 8 and 9 months (0.92, 0.37, 0.31, 0.38 micrograms/l respectively; pooled S.E.M. = 0.12). After castration mean LH levels did not differ with age. Mean FSH levels did not differ among age groups either before or after castration. Increased serum LH levels in 4-month-old bulls confirmed the transient rise in LH secretion that occurs at this time in developing bull calves.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival after percutaneous endoscopic gastrostomy among older residents of Quebec.

CONTEXT: Percutaneous endoscopic gastrostomy has become a mainstay of nutritional support for individuals with swallowing dysfunction. There is little population-based data to guide the use of this intervention in older individuals. OBJECTIVE: To describe the use of percutaneous endoscopic gastrostomy among older residents of Quebec and to evaluate patient characteristics associated with subsequent survival and hospital discharge. DESIGN: A population-based cohort study. SETTING: Quebec, Canada. PATIENTS: 175 individuals with a billing claim for percutaneous endoscopic gastrostomy performed in 1993. MEASUREMENTS: Billing and hospitalization databases were used to collect patient characteristics, medical diagnoses, discharge destinations, and dates of death. The relationships between demographic and diagnostic variables before gastrostomy, and subsequent survival and discharge home, were evaluated using survival analysis. RESULTS: Median survival after gastrostomy was 210 days. Mortality at 30 days was 18.3%. Decreased survival was associated with a previous diagnosis of malignancy (risk ratio (RR) = 1.71; 95% CI, 1.09-2.68); mortality did not increase with increasing age. Of 163 individuals hospitalized at the time of gastrostomy, 42 (26%) were discharged home. Individuals with a previous diagnosis of stroke (RR = 2.80; 95% CI 1.01-7.77) were more likely to be discharged home than other individuals. CONCLUSIONS: Survival after percutaneous endoscopic gastrostomy is poor; the requirement for such a procedure appears to be a marker for severe underlying disease. The greater likelihood of return home after gastrostomy among individuals with stroke suggests that the use of this intervention as an adjunct to rehabilitation is appropriate in these individuals.

Protein synthetic patterns in immature and mature human oocytes.

A preliminary study of protein synthesis and amino acid transport in human oocytes was initiated. Qualitative patterns or protein synthesis were examined in individual oocytes cultured in medium containing radiolabeled methionine. The protein synthetic profile of immature oocytes, resolved by one-dimensional electrophoresis and fluorography, was observed to change markedly following germinal vesicle breakdown and oocyte maturation. No further differences in the one-dimensional protein synthetic patterns were observed in mature oocytes maintained in culture from 10 hours up to as long as 50 hours. The protein synthetic pattern of follicular cells was observed to be distinct from that of oocytes and was characterized by the predominant synthesis of a polypeptide with Mr = 44,000. Based on the specific activity of the methionine precursor, the absolute rate of synthesis was calculated to be about 50 pg protein/oocyte/hour. Total protein content was measured to be about 150 ng/egg. Competition of methionine uptake by leucine, efflux of radiolabeled methionine from preloaded oocytes into medium containing methionine and uptake of methionine in medium with low sodium ion concentration was observed. These findings are consistent with the presence of an L (leucine-preferring) system for neutral amino acid transport, similar to that in mouse and rabbit eggs. These studies provide basic data for further analysis of oocytes and perhaps preimplantation-stage embryos in the future.

Development of a quality of care measurement system for children and adolescents. Methodological considerations and comparisons with a system for adult women.

OBJECTIVES: To describe the development of a pediatric quality of care measurement system designed to cover multiple clinical topics that could be applied to enrollees in managed care organizations and to compare the development of this system with the concurrent development of a similar system for adult women. DESIGN: Indicators were developed for 21 pediatric (ages 0-18 years) clinical topics and 20 adult (ages 17-50 years) women's clinical topics. Indicators were classified by the strength of evidence supporting them. A modified Delphi method was used to obtain validity and feasibility ratings from a pediatric expert panel and an adult women's expert panel. Indicators were categorized by type of care (preventive, acute, or chronic), function (screening, diagnosis, treatment, or follow up), and modality (history, physical examination, laboratory/radiology study, medication, other intervention, or other contact). RESULTS: Of 557 pediatric and 391 adult women's proposed indicators, 453 (81%) and 340 (87%), respectively, were retained by the 2 expert panels. A lower percentage of final pediatric indicators than adult indicators were based on randomized, controlled trials and other rigorous studies (18% vs 40%, P < .001). The expert panels were more likely to retain indicators based on rigorous studies (93% retained) than on descriptive studies and expert opinion (81% retained, P < .001). A higher percentage of pediatric indicators than women's indicators were for preventive care (30% vs 11%, P < .001) and a lower percentage were for acute care (36% vs 49%, P < .001) or chronic care (34% vs 41%, P = .06). CONCLUSIONS: This study contributes to the field of pediatric quality of care assessment by providing many more indicators than have been available previously and by documenting the strength of evidence supporting these indicators. Formal consensus methods are essential for the development of pediatric quality measures because the evidence base for pediatric care is more limited than for adult care.

Reductions in cost and cesarean rate by routine use of external cephalic version: a decision analysis.

OBJECTIVE: To describe currently accepted methods for managing the term breech pregnancy, and to predict the delivery outcomes and costs of each method. METHODS: Literature review was used to derive four options for the peripartum management of the term breech pregnancy. Using decision-analysis techniques, we calculated the predicted delivery outcomes and costs associated with each option. RESULTS: Applying external cephalic version to all term breech pregnancies without contraindications to labor or version, and allowing a trial of labor for eligible women who fail version, results in a 25% cesarean rate, at a cost of $8071 per case. Delivering unsuccessful versions by scheduled cesarean results in a 32% cesarean rate, at a cost of $8276 per case. In contrast, a strategy not using external version but allowing a trial of labor for those mothers who meet eligibility criteria results in a 63% cesarean rate, at a cost of $8755 per case. Routinely scheduling a cesarean when a breech is identified at term results in an 89% cesarean rate, at a cost of $9544 per case. CONCLUSIONS: Although the liberal use of vaginal delivery for term breech pregnancies has been suggested as one way of lowering the cesarean rate, the addition of routine external cephalic version to the management strategy will result in more vaginal deliveries and lower costs than strategies that allow vaginal delivery but do not include an attempted cephalic version. Routine cesarean without attempted external cephalic version results in excessive operative deliveries.

Research design and methods of quantitative synthesis of medical evidence.

OBJECTIVE: To review the scientific principles, strengths, and limitations of research designs and methods of quantitative synthesis of medical evidence. DATA SOURCES: We used MEDLINE to perform a systematic search for literature using the keywords research design, epidemiology, and biometry. Journals searched included six major journals in obstetrics and gynecology and three in general medicine. These sources were supplemented with texts and reviews from the general medical literature. METHODS OF STUDY SELECTION: We reviewed the publications identified by our search and evaluated critically the relevant reports. We summarized objectives and scientific guidelines for the common research methodologies and outlined their advantages and disadvantages. TABULATION, INTEGRATION, AND RESULTS: The standard of clinical research design is the randomized controlled trial (RCT), which, if performed with sufficient methodologic rigor, is least likely to have serious biases. Cohort, case-control, and cross-sectional studies are common observational studies used in reproductive health; such observational studies are more susceptible to biases that can distort the researcher's results and conclusions. Descriptive studies such as case series and case reports are often interesting as clinical vignettes but have limited scientific merit. Methods for quantitative synthesis of medical evidence, including meta-analysis, decision analysis, and cost-effectiveness analysis are being used with increased frequency in the reproductive health literature to summarize medical evidence. CONCLUSION: Various research methods have their own inherent advantages and disadvantages. An understanding of the scientific principles of these methods will enable the clinician to evaluate medical evidence critically.

A meta-analysis of infant outcomes after breech delivery.

OBJECTIVE: To estimate the risks of neonatal morbidity and mortality associated with a trial of labor and with elective cesarean for the term breech infant. DATA SOURCES: Using the terms "breech," "malpresentation," and "external cephalic version," we used the MEDLINE and Health Planning and Administration data bases to search the English-language literature from January 1981 to June 1993. The search was supplemented with a review of the reference lists of key articles and text chapters. METHODS OF STUDY SELECTION: We included randomized trials or cohort studies that specified selection criteria for a vaginal delivery, provided detailed outcome data, and allowed for analysis by intended mode of delivery. DATA EXTRACTION AND SYNTHESIS: Nine studies met the inclusion criteria. We pooled the weighted results from these studies to estimate the risks of birth injuries and perinatal death, and the risk differences between trial of labor and no trial of labor groups. The pooled risk for any injury was 1.00% after a trial of labor and 0.09% after elective cesarean. For any injury or death, the risk was 1.23% after a trial of labor and 0.09% after elective cesarean. The risk differences for injury and injury or death were 0.89 and 1.10%, respectively. These are significantly different from zero, suggesting an increased risk of injury and injury or death after a trial of labor. CONCLUSION: When management decisions are made, the potential increased risk of neonatal morbidity after a trial of labor should be considered along with the increased maternal risk from cesarean delivery.

Lack of progress in labor as a reason for cesarean.

OBJECTIVE: To estimate the prevalence of lack of progress in labor as a reason for cesarean delivery and to compare published diagnostic criteria with the labor characteristics of women with this diagnosis. METHODS: We reviewed medical records and did a postpartum telephone survey to collect data from 733 women who delivered full-term, nonbreech infants by unplanned cesarean between March 1993 and February 1994. These were a subset of 2447 births sampled at delivery from 30 hospitals in Los Angeles County and Iowa. We measured the proportion of unplanned cesareans done for lack of progress in labor, the cervical dilatation at the time of cesarean, length of the second stage, and slope of the active phase among the women. We estimated the proportion of these cesareans that conformed to the ACOG criteria for the diagnosis of lack of progress. RESULTS: Lack of progress was a reason for 68% of unplanned, vertex cesareans. At least 16% of the subjects who had cesareans for lack of progress were in the latent phase of labor according to ACOG criteria. The second stage was not prolonged in 36% of the women who delivered at 10 cm. CONCLUSION: Lack of progress in labor is a dominant reason for cesarean delivery. Many cesareans are done during the latent phase of labor, and in the second stage of labor when it is not prolonged. These practices do not conform to published diagnostic criteria for lack of progress.

Heat-stable regulatory factors are associated with polycation-modulable phosphatases.

Several protein phosphatases which we designated PCM-I, PCM-II and PCM-IId were identified in preparations from aortic smooth muscle. A unique feature of these enzymes is that phosphatase activities expressed against different substrates are subject to modulation by polycationic effectors such as polylysine and lysine-rich histone-H1. They can be distinguished from each other by virtue of significant quantitative differences regarding (a) relative substrate specificities exhibited against phosphorylated myosin light chains, phosphorylase, and inhibitor-1, (b) apparent molecular weights as determined by sucrose density centrifugation, and (c) differential susceptibility to polylysine-mediated modulation of phosphatase activities. Surprisingly, gel filtration of the very same PCM-phosphatase preparation yields either of two apparently different enzymes: namely PCM-II, or PCM-IId. The enzymes appear similar in that low concentrations of polylysine (0.03-0.13 microM) inhibit dephosphorylation of light chains by either enzyme and high concentrations inhibit dephosphorylation of phosphorylase a. However, PCM-II exhibits higher basal phosphatase activity against myosin light chains (480 U/mg) than against phosphorylase a (175 U/mg). In contrast, PCM-IId is more effective in dephosphorylating phosphorylase a (180 U/mg) than in dephosphorylating the light chains (88 U/mg). Moreover, phosphorylase phosphatase activity of PCM-II is biphasically stimulable by low concentrations of polylysine (0.01-0.5 microM), but no stimulation is seen with PCM-IId. In addition, earlier studies with PCM-I showed that, unlike either PCM-II or PCM-IId polylysine biphasically stimulated the dephosphorylation of both phosphorylase a and the myosin light chains. Nevertheless, in spite of these obvious differences between the enzymes other data suggests that the PCM-phosphatases may be related to each other. Incubation of PCM-II at 90 degrees C for 10 min apparently releases heat-stable regulatory proteins which reverse the modulatory effects of polylysine on light chain and phosphorylase phosphatase activities expressed by either PCM-II or PCM-I. Similarly, heat-stable proteins released from PCM-I also reverse polylysine-mediated modulation of both PCM-I and PCM-II. These findings are consistent with a working hypothesis suggesting that PCM-phosphatase may consist of a modulatory domain containing several regulatory proteins and a catalytic domain.(ABSTRACT TRUNCATED AT 400 WORDS)