Biomedical subjects
A M Walker
Publications and source records attributed to A M Walker.
Methods for investigating localized clustering of disease. Historical aspects of leukaemia clusters.
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Patient factors associated with strut fracture in Björk-Shiley 60 degrees convexo-concave heart valves.
BACKGROUND: Previously established predictors of outlet strut fracture in Björk-Shiley convexo-concave (CC) valves include larger valve size, larger opening angle (70 degrees versus 60 degrees), younger age at implant, and date of manufacture. We sought to identify patient characteristics that might be predictive of strut fracture and to refine the estimates associated with previously identified predictors. METHODS AND RESULTS: We conducted a case-control study of CC60 degrees valves implanted in the United States and Canada and manufactured between January 1, 1979, and March 31, 1984. Cases included all valves with verified outlet strut fractures reported to the manufacturer from January 1979 through January 1992. Up to 10 controls were selected for each case. Control valves were matched according to implanting surgeon and were required to have been functioning at least as long as their matched case valves. Case and control medical records were reviewed for information on patient medical history before the valve implant. There were 96 case and 634 control valves for which clinical data were available. Patient age and valve size and implant position were confirmed as important determinants of fracture. There was a strong inverse gradient of risk with age. The risk of fracture was 42% lower for each 10-year increment of patient age at time of implant. Large mitral valves were at greatest risk of strut fracture, with the largest mitral valves (33 mm) estimated to be 33 times more likely to fracture than the smallest (21 to 25 mm) aortic valves. Date of manufacture was also associated with risk; valves welded from mid-1981 through March 1984 were more likely to fracture than those manufactured in 1979 and 1980. Body surface area < 1.5 m2 was associated with 1/16 the risk of body surface area > or = 2.0 m2. No other patient factor was strongly associated with the risk of strut fracture. CONCLUSIONS: Few patient features identifiable in the implant record are predictive of strut fracture. Our analysis supports previous work in identifying valve size, patient age, and date of manufacture as predictors of fracture and adds body surface area. A number of these associations suggest that conditions associated with higher cardiac output may also place patients at increased risk.
Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. A large health maintenance organization cohort study.
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an elevated risk of peptic ulcer and upper gastrointestinal hemorrhage, but published reports have lacked information on rates of outpatient disease, have concentrated on the elderly, and have not provided comparisons of rates for specific types of NSAIDs. METHODS: We compared incidence rates of peptic ulcer and upper gastrointestinal hemorrhage in 68 028 people younger than 65 years who used diclofenac sodium, naproxen, piroxicam, or sulindac, and who were members of a network of health maintenance organizations. We reviewed automated insurance claims data and medical records to ascertain cases and included conditions treated on an outpatient basis. RESULTS: Medical claims data were adequate for crude identification of potential cases, but review of medical records led to rejection of 63% of these, representing either no abnormality or diseases other than peptic ulcer or upper gastrointestinal hemorrhage. Of the total 112 cases, 64 (57%) were treated as outpatients. The crude incidence rate per 1000 person-years in users of any current, recent, or past NSAID was 2.2 and in distant-past users of NSAIDs was 0.75. For diclofenac, naproxen, piroxicam, and sulindac, we found a consistent pattern of decreasing NSAID effects from current to recent to past exposure. The risk of peptic ulcer or upper gastrointestinal hemorrhage was 1.6 cases per 1000 people using NSAIDs. CONCLUSIONS: Combining use of automated claims records with review of medical records promotes efficiency while maintaining specificity of case ascertainment. This study, with 57% of cases treated as outpatients, had results consistent with other published reports that were based on hospitalized patients. Within the limits of statistical error, the incidence rates of peptic ulcer and upper gastrointestinal hemorrhage appeared to be similar for the various NSAIDs studied.
Discontinuation of antihyperlipidemic drugs--do rates reported in clinical trials reflect rates in primary care settings?
BACKGROUND: Discontinuation rates for drugs used to treat chronic conditions may affect the success of therapy. However, the discontinuation rates reported in clinical trials may not reflect those in primary care settings. METHODS: We conducted a cohort study using computerized research files and medical records on 2369 new users of antihyperlipidemic therapy at two health maintenance organizations (HMOs) from 1988 through 1990. The rates of drug discontinuation in these primary care settings were compared with the rates reported in clinical trials published from 1975 through 1993, located with the Medline data base. RESULTS: In the HMOs, the one-year probability of drug discontinuation was 41 percent for bile acid sequestrants (95 percent confidence interval, 38 to 44 percent), 46 percent for niacin (95 percent confidence interval, 42 to 51 percent), 15 percent for lovastatin (95 percent confidence interval, 11 to 19 percent), and 37 percent for gemfibrozil (95 percent confidence interval, 31 to 43 percent). For the bile acid sequestrants, niacin, and gemfibrozil, the risks of discontinuation were substantially higher in the HMOs than in randomized clinical trials, in which the summary estimates of this risk were 31 percent, 4 percent, and 15 percent, respectively, for trials of one year or longer. The rates of discontinuation in open-label studies were similar to those in the HMOs. CONCLUSIONS: The discontinuation rates reported in randomized clinical trials may not reflect the rates actually observed in primary care settings. The effectiveness and tolerability of antihyperlipidemic medications should be studied further in populations that typically use the agents.
Low power and striking results--a surprise but not a paradox.
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Prolactin-immunoglobulin G complexes from human serum act as costimulatory ligands causing proliferation of malignant B lymphocytes.
Several lines of evidence indicate that immunoglobulin-bound prolactin found in human serum is not a conventional complex between an anti-prolactin antibody and prolactin but a different type of association of prolactin with the Fab portion of IgG heavy chains. The complex of prolactin with IgG was purified from serum by anti-human prolactin affinity chromatography and was shown to contain close to 1 mole of N epsilon-(gamma-glutamyl)lysine crosslinks per mole of complex, a characteristic feature in structures crosslinked by transglutaminase. Interestingly, the complex caused a proliferation of cells from a subset of patients with chronic lymphocytic leukemia, while it was inactive in a cell proliferation prolactin bioassay. By contrast, human prolactin stimulated the proliferation of cells in the bioassay but had no effect on the complex-responsive cells from the patients. Competition studies with prolactin and free Fc fragment of IgG demonstrated a necessity for engaging both the prolactin and the immunoglobulin receptors for proliferation. More importantly, competition for the growth response by free prolactin and IgG suggests both possible reasons for the slow growth of this neoplasm as well as avenues for control of the disease.
Toxoplasma infection among pregnant women in Switzerland: a cross-sectional evaluation of regional and age-specific lifetime average annual incidence.
A simple generalized linear model of toxoplasmosis incidence has been applied to serologic data from more than 9,000 women who delivered babies in Switzerland. This model, based on an assumption of constant incidence of toxoplasmosis throughout time and ages, yields estimates of incidence rates that show marked contrasts between subgroups of women categorized on the basis of their geographic origin and duration of residence in Switzerland. The patterns observed are in agreement with previously reported data from specific areas. When applied to Swiss resident women of different age groups, the average incidence rate estimates obtained were remarkably similar. This was not the case among the subgroup of Portuguese immigrant women, nor when the model was applied to previously published data from Sweden where toxoplasmosis incidence has clearly decreased in the last 20 years. Although models for the analysis of cross-sectional data involve major simplifying assumptions, it appears that they can yield useful epidemiologic information and that departures from the assumed simplified structure of the data can sometimes be identified.
The infrequency of liver function testing in patients using nonsteroidal anti-inflammatory drugs.
OBJECTIVE: To describe the monitoring of liver function for patients using nonsteroidal anti-inflammatory drugs (NSAIDs), we reviewed the patterns of liver function testing in a medium-sized health maintenance organization. METHODS: We examined the interval between start of therapy and first performance of a liver function test during courses of therapy of the NSAIDs diclofenac sodium, naproxen and naproxen sodium, and piroxicam. For comparison, we also studied courses of lovastatin as a "positive control," in which the anticipated frequency of liver function testing was high. RESULTS: The frequency of liver function tests in patients using NSAIDs was generally low, although testing was more common in patients who used diclofenac. The probability of liver function testing was higher for patients treated in recent calendar years, for patients treated by rheumatologists, for patients who previously used NSAIDs, and for patients who had undergone a liver function test sometime in the 6 months preceding the onset of therapy. CONCLUSION: Physicians ordered liver function tests less frequently than recommended, but the observed testing patterns appear rational in light of the very low reported frequency of serious hepatic disease in large, monitored populations of patients using NSAIDs.
Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization.
OBJECTIVE: To quantify the incidence of symptomatic hand, hip, and knee osteoarthritis (OA) among members of the Fallon Community Health Plan, a health maintenance organization located in central Massachusetts. METHODS: Incident OA was defined as the first evidence of OA by radiography (grade > or = 2 on the Kellgren-Lawrence scale of 0-4) plus joint symptoms at the time the radiograph was obtained or up to 1 year before the radiograph was obtained. RESULTS: The age- and sex-standardized incidence rate for hand OA was 100/100,000 person-years (95% confidence interval [95% CI] 86, 115), for hip OA 88/100,000 person-years (95% CI 75, 101), and for knee OA 240/100,000 person-years (95% CI 218, 262). The incidence of hand, hip, and knee OA increased with age, and women had higher rates than men, especially after age 50. A leveling off or decline occurred for both groups around the age of 80. CONCLUSION: In a large study of symptomatic OA we observed incidence rates that increased with age. In women ages 70-89, the incidence of knee OA approached 1% per year.
Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs.
Although the etiologic relation between nonsteroidal antiinflammatory drug (NSAID) use and gastrointestinal lesions is well documented, newly introduced NSAIDs deserve a fresh examination for their risk/benefit ratio. To estimate the association between consumption of ketorolac and the occurrence of gastroduodenal lesions, we conducted a case-control study. The study population comprised 600 outpatients with a confirmed endoscopic diagnosis of ulcer and erosion in 1991 and 1992 and 6,000 community controls matched by age and sex. We retrieved the prescription history through a computerized prescription monitoring system. We defined exposure to each study drug as "current" (month of endoscopy and preceding month), "recent" (second or third month preceding endoscopy). and "past" (fourth to sixth month preceding endoscopy). Current users of NSAIDs showed a 30% increase in the incidence of gastroduodenal lesions [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.98 - 1.8] after adjustment for recent or past use of any NSAID, recent or past gastrotoxic therapy, recent or past use of gastroprotective drugs, and recent or past use of any other drug. Among NSAIDs, ketorolac was the only one showing a distinctly elevated risk of gastroduodenal lesions (OR = 4.2; 95% CI = 1.9-9.4). Current use of any NSAID was associated with almost a doubling of risk for ulcer alone (OR = 1.9; 95% CI = 1.3-3.0); no elevation in risk was found for erosions. The adjusted relative risk for ulcer associated with current use of ketorolac was 9.8 (95% CI = 3.4-28.10. Recent and past use of NSAIDs does not increase the risk of ulcer.(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term survival in the Wolf-Hirschhorn (4p-) syndrome.
The clinical features of Wolf-Hirschhorn syndrome are described in a 29-year-old woman who shows severe retardation of growth and development. It is important for health care professionals involved with families in which this condition is present to realize that long-term survival may occur.
Continuous measurement of blood flow in the superior sagittal sinus of the lamb.
We assessed the validity of recording blood flow in the superior sagittal sinus (Qss) as a measure of cerebral blood flow (CBF). While anesthetized, 10 lambs were instrumented with a transit-time ultrasonic flow probe around the superior sagittal sinus to measure Qss, electrodes to assess sleep state, catheters to measure cerebral perfusion pressure (Pcp), and an occlusive cuff around the common brachiocephalic artery to vary blood pressure. After 72 h recovery, lambs were studied during spontaneous sleep-wake cycles to establish 1) the normal range of Qss and 2) the response rate of Qss to rapid alterations of Pcp. Subsequently, the lambs were reanesthetized, and the measurement of Qss was calibrated and validated. Qss was linearly related to the arterial inflow of 35% of the brain mass (y = 0.5 x + 1.6, r = 0.93, n = 4). Qss was greater in active sleep (154.1 +/- 45.7 ml.min-1 x 100 g-1, mean +/- SD, n = 5) than in quiet sleep (97.1 +/- 40.8 ml.min-1 x 100 g-1) and quiet wakefulness (107 +/- 44.3 ml.min-1 x 100 g-1, P < 0.05). Qss responded rapidly (within one beat) to spontaneous and to induced transient changes in Pcp. We conclude that recording blood flow in the superior sagittal sinus provides a simple, continuous, and quantitative measure of CBF from a defined area of the brain and is appropriate for studying transient changes in the cerebral circulation.
Manufacturing characteristics associated with strut fracture in Björk-Shiley 60 degrees Convexo-Concave heart valves.
Björk-Shiley Convexo-Concave (CC) valves sometimes experience fracture of the outlet strut. Previously implicated valve characteristics that predict strut fracture include larger valve size, larger opening angle (70 degrees vs 60 degrees), remilling, weld date, and implant in the mitral position. While the associations between risk, size, and opening angle suggest that part of the elevated incidence of strut fracture might be due to the design of the Björk-Shiley valves, only a small fraction of implanted valves have experienced strut fracture. In consequence, previously unexamined variations in the manufacturing process have been suggested as possible factors affecting the failure risk of individual valves; materials, manufacturing steps, quality control, and specific workers have all been put forward as potential explanations for valve-to-valve variation in risk. We conducted a case-control study of CC60 degrees valves implanted in the USA and Canada and manufactured between January 1, 1979 and March 31, 1984. Cases included all verified strut fractures reported to the manufacturer from 1979 through January, 1992. up to 10 controls were selected for each case. Controls were matched to cases on implanting surgeon and were required to have been implanted and functioning at least as long as their respective case valves. We reviewed case and control manufacturing records. There were 150 cases and 1095 surgeon-matched controls. Large mitral valves were at greatest risk of strut fracture; 33mm mitral valves were estimated to be 23 times more likely to fracture than 21-25mm aortic valves. Valves welded in 1979 and 1980 were less likely to fracture than those welded in any other time period; however, no specific manufacturing procedures or personnel were uniquely associated with this time period. Valves with more flexible outlet struts, as determined by the hook deflection and load deflection tests during manufacture, appear to have been at higher risk than valves with more rigid outlet struts. There were three welders who had worked on a sufficient number of valves to allow separate estimation of the risk in the valves they welded. One welder's work was associated with about one-third the risk of valves worked on by the other two. Examination of receiver operating characteristic curves revealed, however, that welder identity added little to the discriminating information already available in the form of valve size and implant position. It is concluded that welder identity and strut flexibility appear to contribute to the risk of outlet strut fracture in Björk-Shiley CC60 degrees valves. Neither of these factors, however, is sufficient to account for much of the previously unexplained variation in risk. No other characteristic measurable in existing manufacturing records appears to predict risk of strut fracture in any useful way.
The lag time between onset of symptoms and diagnosis of rheumatoid arthritis.
OBJECTIVE: Rheumatoid arthritis (RA) may be biologically reversible if treated in the first several months, yet it is unknown whether patients are diagnosed that early. We investigated the lag time between symptom onset and diagnosis of RA in a population with excellent access to rheumatology care. METHODS: Using review of medical records, we evaluated all patients newly diagnosed as having RA from 1987 through 1990, at a health maintenance organization in central Massachusetts. Total lag time from symptom onset to first definite diagnosis was divided into medical encounter lag time (from symptom onset to first medical encounter) and diagnosis lag time (from first medical encounter to diagnosis). RESULTS: The median total lag time was 36 weeks (range 4 weeks to > 10 years). The median medical encounter lag time was 4 weeks (not all patients included in the analysis). The median diagnosis lag time was 18 weeks. Diagnosis lag time was shorter for patients with progressive disease and positive rheumatoid factor on the initial test. Of 25 patients with symmetric arthritis and positive rheumatoid factor, only 5 (20%) were diagnosed within 2 months, and 10 (40%) were diagnosed more than 6 months after symptom onset. CONCLUSION: RA diagnosis is usually delayed for several months after symptoms begin, in large part because of delay in diagnosis by the physician. Thus, the goal of initiating treatment extremely early may be unrealistic for most patients.
Respiratory muscle blood flow in the fetal lamb during apnoea and breathing.
We measured blood flow to the respiratory muscles of the fetal lamb using the radioactively-labelled microsphere technique in order to assess whether fetal breathing is an energetically costly activity as has been reported. Diaphragm flow ranged from 6.4-35.2 ml.min-1.100 g-1 during fetal apnoea and rose to 21.1-615 ml.min-1.100 g-1 during fetal breathing (P < 0.02; n = 7). Parasternal muscle flow also increased significantly (P < 0.02) between fetal apnoea and breathing while external and internal intercostal flows did not change. Expressed as a percentage of cardiac output the diaphragm received 0.08-0.28% during apnoea and 0.22-2.2% during fetal breathing. Neither placental blood flow nor fetal O2 consumption increased significantly between fetal apnoea and breathing. We conclude that the levels of perfusion required by the respiratory muscles for breathing in the fetus are inconsistent with fetal breathing costing a large proportion of the fetal O2 budget.
Normal early infant behaviour patterns.
As part of a wider study, infant behaviour was reviewed prospectively, using a 24 h diary completed by the mother. Infants' sleep, awake, fussing, crying and feeding behaviour were recorded at 1,2,4,6 and 8 weeks. Completed records were obtained from 21 infants. As expected most time was spent asleep, with a mean of 16.2 h at 1 week and 15.5 h at 8 weeks. Most sleeping occurred between midnight and 4 a.m. even by week 1 and there was a progressive fall in the average duration of feeding during that time interval over the 8 week period. Fussing and crying were mostly noted between 4 and 8 p.m. with an additional peak between 8 a.m. and noon, the latter disappearing by week 4. There was also a progressive drop in both the average feeding and fussing/crying times by week 8, reflecting increased settled and awake periods. It is against a background of normal early infant behaviour patterns that one can evaluate interventions aimed at altering such behaviour and dealing with the vexed problem of 'colic'.
Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities.
The incidence of transient hypogammaglobulinaemia of infancy (THI) detected in a major paediatric centre over a 10 year period was examined. A total of 2468 subjects less than 2 years of age had an IgG measurement taken between July 1979 and March 1990. Subjects with known immunodeficiencies were excluded. Fifteen patients were classified as having THI with an initial IgG level less than the fifth centile followed by a second measurement within the normal range. A further 24 patients were identified as having possible THI with a single low IgG concentration. There were 60,174 live births each year in Victoria in the years 1979-88. This gives an incidence of proved THI of 23 per 10(6) births, and including proved and probable THI an incidence of 61 per 10(6) live births. Of those patients with proved THI 12/15 had symptoms of either atopic disease or food allergy/intolerance and three had gastrointestinal symptoms without any evidence of atopic disease. At presentation 12/15 (80%) were IgA deficient and 9/15 had IgM concentrations less than the 20th centile for age. It is suggested that in view of the preponderance of atopic and food intolerant patients that subclinical protein loss from the bowel due to allergic inflammation may be a contributing factor to the development of THI in some patients.