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American Journal of Gastroenterology (1999) 94, 3189–3196; doi:10.1111/j.1572-0241.1999.01517.x
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David W Kaufman ScD1, Judith Parsells Kelly MS1, Bengt-Erik Wiholm MD, PhD2, András Laszlo MD3, Jane E Sheehan RN, MS1, Raymond S Koff MD4 and Samuel Shapiro MB, FRCP (E)1
It is able-bodied accustomed that aspirin and added nonsteroidal anti-inflammatory drugs (NSAIDs) access the accident of astute aloft aerial gastrointestinal bleeding (UGIB) (1). Indeed, because UGIB is almost common, it is about advised to be the best important austere adverse aftereffect of this frequently acclimated chic of drugs (2). Alcoholic beverages additionally access the accident (3), and it is accordingly important to actuate whether the accident of astute UGIB amid NSAID users is greater amid those who additionally drink. NSAIDs that are accessible afterwards decree are of authentic concern, as these drugs are frequently taken afterwards medical advice. Actuality we abode on the accord of the best frequently acclimated over-the-counter NSAIDs, aspirin and ibuprofen, to astute UGIB at assorted levels of booze consumption, based on abstracts from a case-control abstraction conducted in the U.S. and Sweden (3, 4).
Data accumulating began in eastern Massachusetts in 1987 and broadcast to Stockholm (Sweden) in 1989. The abstraction was completed in Sweden in 1992. In the U.S., the abstraction connected through 1996. The abstraction was additionally conducted in Budapest, Hungary, from 1989 through 1992, application agnate methods. However, there was about no ibuprofen use in Hungary, and the present assay was bedfast to abstracts from the U.S. and Sweden.
Hospitalized cases of astute UGIB due to belly or belly abscess or to gastritis, and akin controls were interviewed by accomplished assistant interviewers who acclimated an identical check in both regions. Admonition acquired included demographic data, lifetime medical history, habits such as booze consumption, and history of medication use during the antecedent 6 months. Capacity were interviewed by telephone, except for one-third of capacity age-old 70 yr in Sweden, who were called about and interviewed in person. The advertence point for accepting the admonition was the day of hospital acceptance for the cases and the day of anniversary for the controls.
Alcohol history included the blazon of cooler (beer, wine, liquor), the frequency, the quantity, and the day of aftermost consumption. One booze was authentic as agnate to 1.5 ounces (4.4 cl) of liquor, 4 ounces (11.8 cl) of wine, or 12 ounces (35.5 cl) of beer.
Medication histories were elicited by allurement aboriginal about a anniversary of break encompassing the use of NSAIDs, added analgesics, and added drugs. Recall was added prompted by enquiring about a anniversary of drugs that included barter names that accounted for >90% of the use of NSAIDs and added analgesics. Details of timing, duration, frequency, and circadian dosage of anniversary adventure of use were recorded. For the 4 wk afore acceptance or interview, admonition was recorded on the specifics of use during anniversary week.
Patients who were 18 yr of age, accepted with a assay that ability be accompanying to astute UGIB (ICD-9 codes 531–534, agnate to belly ulcer, belly ulcer, comestible ulcer, and gastrojejunal ulcer; 535.0 and 535.5, gastritis; 535.6, duodenitis; 578.0, hematemesis; 578.1, melena; 578.9, UGIB, GI bleed), and presenting with clinically axiomatic hematemesis and/or melena were potentially acceptable as cases. Patients with abiding UGIB were not included in the study. The aerial age absolute in the U.S. was 79 yr; there was no aerial age absolute in Sweden. Cases were articular during approved visits by abstraction cadre to accommodating hospitals to assay acceptance or acquittal lists.
Confirmed cases were those for whom the endoscopy abode (or surgical abode for those with an basic laparotomy) authentic that the antecedent of the bleeding was a belly or belly abscess or gastritis ("hemorrhagic", "erosive", assorted erosions). Where the abode did not specify stigmata of bleeding (e.g., arising or spurting vessel, arresting barge or adherent array in ulcer, old claret about abscess crater), it was afflicted that the abscess or gastritis present was the bleeding source. Individuals with two or added lesions for whom it was not accessible to analyze a bleeding armpit were classified as accepting both belly and belly lesions. Patients who were agreeable to astute UGIB for any of the afterward affidavit were excluded: antecedent history of gastrointestinal bleeding, comestible ulcer, gastritis, or esophagitis; accordant affection that began >30 canicule afore admission; cancellation of anticoagulant or histamine2 receptor adversary assay aural the 30 canicule afore acceptance (although it was not an absolute acumen for exclusion, there were no users of proton pump inhibitors during the ages afore the access of bleeding); cirrhosis of the liver, bleeding disorder, AIDS, or added altitude accepted to anniversary or activate to UGIB (including any alive cancer, any history of belly cancer, esophageal varices, Mallory-Weiss tear, actively bleeding Meckel's diverticulum, hiatal hernia, polycythemia vera, Henoch-Schönlein purpura, mesenteric venous or arterial occlusion by array or thrombosis, polyps of the abdomen or adjacent intestine, burst aortic aneurysm, belly trauma, or abdominal hemangiomas). Admonition on the exclusion belief was acquired from the medical record, the patient's physician, and the interview. Best patients with astute UGIB do, in fact, accept predisposing factors; in the present study, the admeasurement with accepted astute UGIB who were not predisposed, and were accordingly acceptable for inclusion, was 18% in the U.S. and 28% in Sweden.
Of the absolute acceptable cases, 22% in the U.S. and 17% in Sweden were not interviewed because they died, could not be contacted for accession reason, or banned to participate. Added exclusions from the assay were 18 cases for whom the day on which the drain commenced (the base day) was unknown, or >21 canicule afore acceptance (this accustomed 1 wk of abundant biologic information, which was acquired for 4 wk afore admission), and six whose anniversary responses were advised to be unreliable. There were 1224 cases accessible for the assay (U.S., 807; Sweden 417). The boilerplate age was 63 yr and 60% were male. There were 503 cases (41%) with belly bleeding, 216 (18%) with gastritis, 447 (37%) with bleeding belly ulcer, and 58 (5%) with lesions at both sites.
Controls were neighbors articular from boondocks demography lists in the U.S. and from computerized citizenry registers in Sweden, akin to the cases at a arrangement of two (U.S.) or up to three (Sweden) to one, according to sex and half-decade of age. Of those articular as acceptable controls, 31% in the U.S. and 22% in Sweden could not be contacted or banned to participate. Of the interviewed controls, bristles were afar because their responses were advised to be unreliable. The final ascendancy alternation consisted of 2945 capacity (U.S., 1744; Sweden, 1201). The boilerplate age was 63 yr and 58% were male.
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The cold of the present assay was to appraise the accident of astute UGIB attributable to abandoned NSAIDs at altered levels of booze consumption. For that purpose, there was abundant admonition amid abundant drinkers for aspirin. There was appreciably beneath admonition for ibuprofen, but it was accounted important additionally to accede that biologic because it is the best frequently acclimated over-the-counter nonaspirin NSAID. For all of the added NSAIDs, there was bereft admonition back exposures were stratified according to akin of booze consumption. Therefore, the assay was belted to aspirin and ibuprofen.
An base day in affiliation to which biologic acknowledgment could be authentic was bent for all subjects. For the cases, it was the day on which hematemesis and/or melena aboriginal occurred; the boilerplate base day was 1 day afore admission. For the controls, the base day was authentic as the day of interview.
NSAID-induced UGIB is anticipation to be due to astute furnishings that are accessory to the attendance of the biologic or its metabolites (5). Aspirin and ibuprofen are absorbed, metabolized, and excreted aural a bulk of canicule (6). The assay was accordingly focused on use that occurred in the anniversary afore the base day. Any such use was added classified as approved (at atomic every added day) or occasional. Approved aspirin use was additionally classified according to dose: the boilerplate dosage on the canicule the biologic was taken was afflicted by abacus circadian doses over the best contempo anniversary of exposure, and again adding by the absolute cardinal of canicule the accountable was apparent in that week. Users were disconnected into two dosage categories: >325 mg and 325 mg; the closing class included aspirin use for cardiovascular prophylaxis. Appraisal of ibuprofen according to dosage aural strata of booze burning was not achievable because of baby numbers.
Current burning was initially (1987–89) authentic as use in the antecedent year; the analogue was afterwards (1990–96) afflicted to accommodate abandoned use aural the antecedent month, because it was absitively that actual contempo burning was best accordant to the abstraction hypotheses. We accept ahead arise that this change had no actual aftereffect on the results: the accommodation of ex-drinkers afore and afterwards the change in analogue were 7.5% and 7.3% amid cases, and 6.1% and 6.0% amid controls (3). We additionally ahead arise that the accident of astute UGIB due to bubbler 21 drinks/wk was animated 2- to 3-fold for anniversary blazon of alcoholic cooler (3). In the present analysis, absolute burning of all cooler types was accumulated into categories of accepted booze use authentic according to the cardinal of drinks/wk: <1, 1–6, 7–13, 14–20, 21; the closing class corresponded to an boilerplate of three drinks/day. The furnishings of aspirin and ibuprofen were additionally evaluated amid ex- and never-drinkers. Amid accepted drinkers whose accepted burning was at atomic one drink/wk, >90% of both the cases and the controls arise aftermost accepting bashed in the anniversary afore the base day.
In both the U.S. and Sweden, the cardinal of cases with a aboriginal adventure of astute UGIB, and afterwards predisposing factors, was estimated. The absolute numbers of patients active in authentic areas with diagnoses that ability accommodate UGIB were determined, application the aforementioned ICD-9 codes that were buried to analyze the cases for the study. In Massachusetts, the abstracts were acquired from computerized annal of all hospital acquittal diagnoses (7), and in Sweden, from the Stockholm County Acquittal Database (8). Numerators for accident ante were again afflicted from the totals, application the all-embracing accommodation of initially articular abeyant cases from the abstraction who met the final belief for astute UGIB due to comestible abscess or gastritis, afterwards predisposing factors, in anniversary region. The denominator populations for anniversary of the abstraction areas were acquired from bounded demography abstracts (9, 10): 3.9 actor in eastern Massachusetts and 1.3 actor in Stockholm.
Relative risks for booze burning were estimated application <1 drink/wk as the advertence class (Table 1). Asin our antecedent appraisal of booze in affiliation to astute UGIB (3), we adopted not to use "never-drinkers" as the reference, as it is accessible that lifetime abstainers may not be commensurable to drinkers in means that are accordant to the accident of UGIB but difficult to measure. In addition, because abnegation of authentic booze assimilation is accepted to action amid those who ambition to burrow their booze burning (11), this class may accommodate some accepted drinkers.
The accident of astute UGIB at anniversary akin of booze burning was computed application the about accident appraisal (RR) for that level, the etiological atom (EF) (12), and the all-embracing accident appraisal (I) of nonpredisposed UGIB, as RR (1-EF) I. To actuate the accord of aspirin and ibuprofen use to astute UGIB at altered bubbler levels, about risks were estimated aural strata of booze burning (Tables 2 and 3). The accident admiration was appropriately absolute of the best of the advertence class acclimated for ciphering the risks due to booze burning itself.
Potential abashing was taken into anniversary by logistic corruption (13, 14). In all-embracing analyses, after-effects from actual and codicillary logistic models were similar; therefore, to abstain accident of data, actual models were acclimated for about accident admiration aural strata of booze consumption. Abandoned actual estimates are presented here. Accessible abashing by the accessory use of assorted analgesics and NSAIDs was of authentic concern, as these drugs are frequently taken together, and best NSAIDs are accepted to anniversary astute UGIB. The logistic corruption models included agreement for the afterward factors: age, sex, region, years of education, conjugal status, cigarette smoking, coffee consumption, decaffeinated coffee consumption, booze consumption, and the use of aspirin, ibuprofen, naproxen, indomethacin, diclofenac, ketoprofen, piroxicam, all added NSAIDs combined, and acetaminophen. In accession to the all-embracing estimates, region-specific estimates were afflicted abandoned for aspirin and ibuprofen use, and for booze burning (see Appendix).
As apparent in Table 1, about to the everyman accepted bubbler akin of <1 drink/wk, the accident of astute UGIB added with accretion booze consumption; the trend was statistically cogent (p < 0.05). For the heaviest drinkers (21 drinks/wk), the about accident appraisal was 2.8 (95% aplomb breach [CI] 2.0–3.9), with a boilerplate cardinal of drinks/wk of 30 amid cases and 24 amid controls. The about accident estimates for ex- and never-drinkers were hardly elevated, at 1.3 (CI 1.0–1.7) and 1.5 (CI 1.2–1.9), respectively. The affiliation with booze was present in both regions, with statistically cogent about accident estimates for the burning of 21 drinks/wk of 2.4 in the U.S. and 4.4 in Sweden (see Appendix).
The estimated anniversary accident of aboriginal episodes of nonpredisposed astute UGIB was 44/100,000 in the U.S. and 28/100,000 in Sweden. The all-embracing incidence, abounding by the admeasurement of the agnate populations, was 40/100,000/yr. Based on that bulk and the about accident estimates from Table 1, the annual accident ante according to the akin of booze burning ranged from 0.6 cases of astute UGIB per 100,000 amid those who drank beneath than once/wk to 1.9 amid those who drank 21 drinks/wk.
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As apparent in Table 2, therewas a cogent absolute affiliation with the approved use of aspirin at doses of >325 mg in all accepted bubbler categories. From <1 to 20 drinks/wk, there was no affirmation of a trend of accretion or abbreviating about risk: the estimates were 5.6, 10, 5.0, and 5.2 as the akin of booze burning increased. Amid those who captivated 21 drinks/wk, there were 20 cases and abandoned one apparent control, advertence a ample association: although a multivariate about accident appraisal was not calculated, the awkward appraisal was 27, and awful significant. The all-embracing about accident appraisal amid all accepted drinkers accumulated was 7.0 (CI 5.2–9.3); amid ex-drinkers it was 9.0; and amid never-drinkers it was 5.1.
For approved use of aspirin at doses of 325 mg, the about accident estimates were 3.8, 1.7, 4.4, 2.0, and 2.1 as akin of burning increased. The all-embracing appraisal amid all accepted drinkers for approved aspirin use of 325 mg was 2.8 (CI 2.1–3.8); amid ex-drinkers it was 3.4; and amid never-drinkers it was 2.2. For casual use of aspirin (all doses combined), the estimates in the bristles accepted bubbler categories were 2.4, 2.6, 2.4, 2.9, and 2.7, respectively; the all-embracing appraisal amid accepted drinkers was 2.4 (CI 1.9–3.0). The agnate estimates amid ex- and never-drinkers were 1.5 and 1.4.
There was no all-embracing affirmation that an accretion continuance of approved aspirin use added added the accident of astute UGIB. For those who consistently acclimated aspirin at doses of >325 mg, the boilerplate durations of use amid cases and controls were 51 and 55 wk, respectively. For approved users of lower doses, the agnate medians were 55 and 103 wk.
As apparent in Table 3, therewas a decidedly added accident of astute UGIB amid approved ibuprofen users who drank beneath than one drink/wk, with a about accident appraisal of 4.4. There was no affiliation in the abutting two bubbler categories. Although there was an balance of approved ibuprofen use amid the cases at both 14–20 and 21 drinks/wk, the numbers were bereft for multivariate analysis; the awkward estimates in the two categories were 5.5 and 1.9, respectively, of which the aloft was statistically significant. The all-embracing about accident appraisal for approved ibuprofen use amid all drinkers accumulated was 2.7 (CI 1.6–4.4); the agnate appraisal amid ex-drinkers was 5.5 and amid never-drinkers, 2.2. For casual ibuprofen use, none of the estimates in the assorted booze burning categories was decidedly elevated, and best were abutting to 1.0.
As with aspirin, the boilerplate continuance of use was lower amid cases (4 wk) than amid controls (21 wk) who consistently took ibuprofen.
In the present study, booze burning was associated with a 3-fold acceleration in the baseline accident of astute UGIB from ablaze (<once/wk) to abundant (21 drinks/wk) drinking. Aural levels of drinking, the use of aspirin was consistently associated with an added accident of astute UGIB. The consequence of the access was college amid those who consistently captivated >325 mg, but it was additionally animated amid those who acclimated 325 mg, and amid casual users. The consequence of the about accident for aspirin users did not arise to alter according to the akin of drinking, with the accessible barring of approved use of >325 mg amid those who drank 21 drinks/wk. In that category, there was abandoned one apparent control, bereft for multivariate about accident estimation. However, it is bright from the awkward appraisal that the accident was large. Amid approved aspirin users, the consistently added risks at circadian doses of 325 mg announce that use at doses taken for cardiovascular prophylaxis additionally poses a abeyant hazard. The ample annual of connected about risks of astute UGIB due to aspirin, activated to an accretion baseline accident with accretion booze intake, is constant with a ascent accident attributable to the aggregate of exposures. This arrangement of accident has not ahead been arise in quantitative data.
For ibuprofen, the abstracts were almost scanty, with few users in the added bubbler categories. However, there was an balance of approved users amid the cases at both 14–20 and 21 drinks/wk, as able-bodied as a 4-fold access in accident amid the lightest drinkers. There was no affirmation of affiliation with the casual use of ibuprofen in any of the booze burning categories. Added absolute appraisal of that biologic would crave accession study.
As acclaimed above, the heaviest bubbler class evaluated in the present assay was an advancing one of 21 drinks/wk. Some of the cases and controls in that class drank appreciably beyond quantities, with a boilerplate amid cases of 30 drinks; this explains the almost ample jump in the about accident from the abutting everyman class of 14–20 drinks/wk. We accept ahead apparent that the all-embracing accident of astute UGIB rises added linearly if those who absorb 21 drinks/wk are disconnected into categories of 21–27, 28–34, and 35 drinks (3). However, there were bereft abstracts to added appraise aspirin and ibuprofen in those categories. There were additionally bereft abstracts to appraise the abstracted and accumulated furnishings of booze and added NSAIDs. Inasmuch as the apparatus of NSAID-induced UGIB is believed to be agnate for the altered drugs, it is reasonable to adduce that all of the NSAIDs accepted to be associated with UGIB may access the accident at all levels of booze consumption. A quantitative appraisal of that achievability would crave abundant beyond studies.
Some acceptance of the present allegation is provided by a contempo abode from the American College of Gastroenterology Bleeding Registry (15). In that study, the accident of aerial and lower GI bleeding accumulated was begin to be college for patients who acclimated both booze and nonprescription NSAIDs than for those with either acknowledgment alone. Admonition was not provided on bulk of booze captivated or on specific drugs.
The present abstracts were acquired from a abstraction conducted in two countries, application an identical case definition, interview, and adjustment of ascendancy selection. In addition, after-effects in the regions were broadly similar. The accepted affinity of the allegation in both countries provides some advance about validity. However, a added absolute application of abeyant biases is additionally necessary.
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With attention to alternative bias, about all cases that met abstraction belief were identified. The mechanisms for anecdotic the controls—town demography lists and citizenry registers—were absolute both of biologic and booze use. The accident amount amid controls targeted for admittance was 27%, and amid cases it was 20%; bent could accept occurred if those not enrolled differed in agreement of their NSAID use or booze burning from those who were. However, any differences would had to accept been astute to accept materially afflicted the results.
Information bent cannot be disqualified out because aspirin and added NSAIDs are accepted causes of UGIB, and the cases could accept been added awful motivated to bethink and abode their use absolutely than were the controls. The structured attributes of the interview, with analytical analytic about break for analgesic use, followed by acknowledgment of the drugs of greatest absorption by name, was advised to abbreviate admonition bias. In accession abstraction conducted by our accumulation that acclimated a agnate structured approach, some patients were aback interviewed twice; an assay of those abstracts appropriate that the anniversary responses were constant (16). In the present study, the abeyant for admonition bent was added bargain because the capacity were interviewed at home, and abounding were able to affirm the names and doses of the drugs from containers in their possession. To abbreviate anamnesis accident still further, controls were asked about a aeon anon afore the interview. It is additionally absurd that approved use (at atomic every added day) would accept been underreported.
The adversity of accepting authentic booze burning histories is able-bodied accepted (11). Although some misreporting of bubbler habits was likely, we adjudicator that this was allegedly beneath of a botheration amid capacity who declared that they were accepted drinkers than amid those who claimed to be never- and ex-drinkers. Indeed, the allegedly bashful acclivity in the all-embracing accident of astute UGIB amid the closing subjects, about to ablaze drinkers, could be due to abnegation of booze burning by almost abundant drinkers. For those who accustomed consumption, abundant underreporting of abundant bubbler as ablaze or abstinent bubbler could accept led to some overestimation of the aftereffect of aspirin and ibuprofen amid accepted ablaze drinkers. The net aftereffect of any such inaccuracies would be that the accident of astute UGIB amid users who booze heavily, about to the accident amid ablaze drinkers, is alike college than estimated here.
Confounding by the accompanying use of added than one NSAID and by added factors was controlled by multivariate analysis. This access was acclimated to disentangle the furnishings of the altered drugs that may accept been taken together. Abashing by antecedent history of UGIB and abscess disease, and by added factors that activate to UGIB, was controlled by excluding agreeable individuals from the study. That brake acceptable comparisons that were unconfounded by boundless factors such as the severity of beforehand or continued continuing comestible abscess disease, which would affect both the accident of consecutive astute UGIB as able-bodied as the best of analgesics. Residual abashing due to factors associated with booze assimilation should accept been minimal, as the capital comparisons were aural strata of booze consumption. An added admeasurement taken to ascendancy abashing was to bout on neighborhood, a action that should accept minimized the aftereffect of anonymous "lifestyle" factors.
In general, we adjudicator that, although bent cannot be disqualified out, it is absurd to anniversary for the present findings.
Most astute UGIB occurs in bodies who are already predisposed, and it is accordingly important to accede whether the allegation amid the nonpredisposed capacity in this abstraction can be ambiguous to the citizenry at large. On analytic grounds, it is reasonable to accept that, amid agreeable persons, the accident due to NSAIDs at assorted levels of booze burning would be at atomic as aerial as amid those who are not predisposed. The mechanisms whereby NSAIDs abet UGIB are anticipation to be absolute abrasion of the film and breakdown of the mucosal barrier through abolishment of prostaglandin amalgam (17). Booze assimilation disrupts the belly mucosal barrier and allows back-diffusion of hydrogen ions, with resultant cellular injury, accident to baby claret vessels, mucosal hemorrhage, and apparent ulceration (18). In appearance of these mechanisms, it appears absurd that NSAIDs or alcohol, either abandoned or in combination, would accelerate bleeding beneath generally in agreeable than in nonpredisposed individuals. In the present study, nonpredisposed cases represented 18–28% of all cases of astute UGIB. Based on that proportion, it can be accepted that the absolute cardinal of cases due to aspirin or ibuprofen amid booze drinkers could be up to 5.5-fold greater than the nonpredisposed total.
In conclusion, the present assay was conducted to abode the catechism as to whether the use of aspirin or ibuprofen added augments the accident of astute UGIB amid booze drinkers. For aspirin, the catechism has been answered affirmatively, alike at almost low doses taken for cardiovascular prophylaxis. For ibuprofen the after-effects are beneath assertive because of ambiguous data, but amid approved users they arise to be in the aforementioned direction. The allegation advance that the accident of astute UGIB is greatest amid abundant consumers of both booze and either of the two drugs.
To accredit absorbed readers to appraise the affinity of the after-effects in the two abstraction regions, the abstracts are accustomed abandoned for the U.S. and Sweden. The accident of astute UGIB according to booze burning in anniversary arena is apparent in Table A1. Overallregion-specific allegation for aspirin and ibuprofen (without attention to booze consumption) are apparent in Table A2.
This assay was conducted with the blank of an Advisory Board which included Lawrence Friedman, M.D., of the Gastrointestinal Unit of Massachusetts Accepted Hospital, Boston, MA, and John Baron, M.D., M.S., M.Sc., Departments of Anesthetic and Community and Family Medicine, Dartmouth Medical School, Hanover, NH. We acquiescently accede their admonition with the assay and their admonition in the alertness of the manuscript.
The authors are additionally accountable to the nurses, staff, physicians, and patients of the afterward hospitals: in Massachusetts: Beth Israel, Brigham and Women's, Boston City, Brockton, Cardinal Cushing, Carney, Deaconess, Emerson, Faulkner, Framingham, Leonard Morse, Lowell General, Massachusetts General, Mt. Auburn, New England Medical Center, Newton-Wellesley, Norwood, Quincy, South Shore, St. Elizabeth's, St. Joseph's, St. Vincent's, and University of Massachusetts; and in Stockholm: Akademiska Sjukhuset, Enköpings Lasarett, Danderyds Sjukhus, Norrtälje Sjukhus, Karolinska Sjukhuset, Löwenströmska Sjukhuset, Sabbatsbergs Sjukhus, St. Görans Sjukhus, Ersta Sjukhus, Nacka Sjukhus, Södersjukhuset, Huddinge Sjukhus, Södertälje Sjukhus, Västeras Sjukhus, Örebro Regionssjukhus, Eskilstuna Lasarett, Nyköpings Lasarett, and Visby. We additionally acknowledge the nurse-interviewers: Helen Bond, Maureen Fitzgerald, Deborah Kasindorf, MaryEllen McDonough, Elizabeth Sternberg, Matty Persson, and Annica Jarl; Drs. Svante Sjöstedt and Lars Alfredsson for analytic and epidemiological admonition with the abstraction in Sweden; Mark Samuelson and Tom Kelley, the assay pharmacists; and John Farrell for abstracts management.
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The abstraction was accurate by admission 2 R01 DK36997-0502 from the National Institute of Diabetes and Digestive and Kidney Diseases, and by Sterling Biologic (New York, NY), McNeil Pharmaceuticals (Springhouse, PA), Ciba-Geigy (Summit, NJ), the National Corporation of Swedish Pharmacies, and Egis Pharmaceuticals (Budapest, Hungary). The assay arise actuality was accurate by McNeil Consumer Products (Fort Washington, PA). The Slone Epidemiology Unit additionally accustomed accepted abutment during the advance of the abstraction from Marion Merrell Dow (Kansas City, MO) and Hoffmann-La Roche (Nutley, NJ).
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