Biomedical subjects
Publications and source records attributed to A de Boer.
Simpson's paradox was first recognized at the beginning of the 20th century, but few examples with real data have been presented. In this paper we present an example of this phenomenon from a multicenter study on nosocomial infections, and we try to explain intuitively this type of extreme confounding.
BACKGROUND AND PURPOSE: Despite improved control of blood pressure during the last decades in the United States, a considerable proportion of treated hypertensives have not achieved target blood pressure levels. We estimated the proportion of strokes occurring among treated hypertensive patients that may be attributable to uncontrolled blood pressure. METHODS: A population-based case-control study was conducted among treated hypertensive members of Group Health Cooperative of Puget Sound. Cases were treated hypertensive patients who sustained a first fatal or nonfatal, ischemic (n=460) or hemorrhagic (n=95) stroke during 1989-1996. Controls were a random sample of stroke-free, treated hypertensive Group Health Cooperative enrollees (n=2966), similar in age to the stroke cases. Multiple measurements of blood pressure and other cardiovascular risk factors were collected from medical records. Logistic regression was used to estimate the risk of ischemic stroke and hemorrhagic stroke associated with uncontrolled blood pressure, defined as diastolic blood pressure >90 mm Hg or systolic blood pressure >140 mm Hg. The fraction of strokes attributable to uncontrolled blood pressure among treated hypertensives was calculated. RESULTS: Blood pressure was uncontrolled in 78% of ischemic stroke cases, 85% of hemorrhagic stroke cases, and 65% of controls. After adjustment for potential confounders, uncontrolled blood pressure among treated hypertensive patients was moderately associated with ischemic stroke (risk ratio=1.5 [95% CI, 1.2 to 1. 9]) and strongly related to hemorrhagic stroke (risk ratio=3.0 [95% CI, 1.7 to 5.4]). We estimated that 27% (95% CI, 11% to 39%) of the ischemic strokes and 57% (95% CI, 26% to 75%) of the hemorrhagic strokes among treated hypertensive patients were attributable to uncontrolled blood pressure. Overall, 32% (95% CI, 14% to 45%) of all strokes were attributable to uncontrolled blood pressure. CONCLUSIONS: A considerable proportion of incident strokes among treated hypertensive patients may be prevented by achieving control of blood pressure.
The benefit of pharmacological treatment of hypertension in the prevention of cardiovascular diseases has been established mainly in subjects younger than 80 years of age. The consequences of undertreatment of hypertension with regard to the occurrence of stroke was studied in the Netherlands. About 33% of the hypertensives younger than 80 years and 55% of the hypertensives older than 80 years were not pharmacologically treated, although they were 'candidates' for pharmacological treatment of hypertension. About 19% (n = 1350) of all strokes that occurred in the Netherlands in 1994 among hypertensives younger than 80 years may be attributable to untreated hypertension. Among hypertensives older than 80 years this percentage was 32% (n = 1345). Although the benefit of pharmacological treatment of hypertension in persons older than 80 years has not been established experimentally, the results suggest that a considerable proportion of the strokes among this group of hypertensives may be prevented.
The substitution pattern of anthocyanin pigments is a main determinant of flower color. Flavonoid 3',5'-hydroxylase (F3'5'H) is a cytochrome P450 enzyme (Cyt P450) that catalyzes the 3', 5'-hydroxylation of dihydroflavonols, the precursors of purple anthocyanins. Species such as rose and carnation lack F3'5'H activity and are, therefore, unable to generate purple or blue flowers. Petunia, on the other hand, contains two loci, termed hf1 and hf2, that encode a Cyt P450 with F3'5'H activity. Here we report the identification of an additional petunia gene that is required for 3',5' substitution of anthocyanins and purple flower colors. It encodes a cytochrome b5 and is expressed exclusively in the flower. Inactivation of the gene by targeted transposon mutagenesis reduced F3'5'H enzyme activity and the accumulation of 5'-substituted anthocyanins, resulting in an altered flower color. However, no phenotypic effect on the activity of other Cyt P450s, involved in the synthesis of hormones or general phenylpropanoids, was observed. These data provide in vivo evidence for the regulation of the activity of specific Cyt P450s by a cytochrome b5.
BACKGROUND: Since 1987 the Monitoring Project on Cardiovascular Risk Factors has been carried out in The Netherlands. The purpose of the present study was to assess the agreement between the self-reported questionnaire information that was collected in this survey on cardiovascular diseases and risk factors and information from medical records. METHODS: From 1987 to 1991, over 36,000 men and women aged 20-59 years have participated in the Monitoring Project on Cardiovascular Disease Risk Factors, a cross-sectional population-based study. We compared self-reported information on cardiovascular diseases and risk factors with the general practitioners medical records from a sample of 899 hypertensive subjects. RESULTS: The highest proportion of positive self-reports could be confirmed by the medical records for diabetes conditional on self-report of medication use for this condition (100%), and a history of hypertension conditional on the presence of blood pressure recordings in the medical records (91%). The lowest percentage of positive self-reports confirmed by medical records was a family history of myocardial infarction (3-5%). More than 80% of the negative self-reports were confirmed by the medical records for most conditions, except for history of hypertension, conditional on the presence of blood pressure recordings in the medical records (40%). The overall agreement above chance was substantial for cerebrovascular disease (kappa = 0.78) and diabetes (kappa = 0.75), moderate for myocardial infarction (kappa = 0.55), poor for myocardial infarction of the respondents' father (kappa = 0.07) and mother (kappa = 0.05), and fair to moderate for all other self-reported conditions. CONCLUSION: Agreement between self-reported information and medical records was variable. For further studies, self-reports of cardiovascular diseases and risk factors should preferably be complemented with information from other sources such as medical records.
OBJECTIVE: This study was performed to correlate the changes in concentration of S-100 protein in the cerebrospinal fluid (CSF) during and after thoracoabdominal aortic aneurysm (TAAA) surgery with the results of somatosensory and motor evoked potential monitoring. METHODS: The study was designed as a prospective study at St Antonius Hospital in Nieuwegein, The Netherlands. The participants were 19 patients who were undergoing elective TAAA surgery. CSF samples for analysis of S-100 protein were drawn after the induction of anesthesia, during the cross-clamp period of the critical aortic segment, after 5 minutes of reperfusion of this segment, during the closure of the skin, and 24 hours after the closure of the skin. In all the patients, continuous intraoperative recording of myogenic motor potentials evoked by transcranial electrical stimulation (tcMEP) and somatosensory potentials evoked by stimulation of the posterior tibial nerve took place to monitor the integrity of the spinal cord. The operative technique consisted of staged or sequential clamping to maximize the beneficial effect of the distal perfusion by the left heart bypass, continuous CSF drainage to keep the CSF pressure below 10 mm Hg, and moderate hypothermia (32 degrees C rectal temperature). We correlated the measured concentrations of S-100 protein in CSF with the results of evoked potential monitoring during surgery and the number of intercostals reimplanted and oversewn. RESULTS: In all the patients, the concentration of S-100 protein was increased in CSF. The highest concentration of S-100 protein was found in the CSF sample taken 5 minutes after reperfusion of the critical aortic segment. There was a good (negative) correlation between the changes in S-100 protein in CSF and the changes in motor evoked potential monitoring during the cross-clamp period. The best (negative) correlation was detected between the S-100 protein elevation in the CSF sample drawn 5 minutes after reperfusion and the tcMEP amplitude reduction during clamping (r = -0.73; P =.007). No relation was found between the S-100 protein dynamics in CSF and somatosensory evoked potential monitoring. A positive (r = 0.58; P =.05) correlation was found between the change in tcMEP amplitude during clamping and the number of reattached intercostals. A moderate to good (r = -0.5 to -0.7; P <.05) correlation between the number of reattached intercostals and the changes in S-100 protein concentration in CSF during TAAA surgery was found. Our data show that transient elevations in S-100 protein after cross clamping are larger in those patients with marked decrease in tcMEP from baseline during the cross-clamp period. CONCLUSION: A correlation is shown between an increasing concentration of S-100 protein in CSF and a reduction in tcMEP amplitude during cross clamping of the aorta. The S-100 protein in CSF seems to be a marker of potential clinical value in the evaluation of the effects of procedures to detect and reduce spinal cord ischemia.
Intraoperative recording of myogenic motor responses evoked by transcranial electrical stimulation is a method of controlling the integrity of the motor pathways during clamping of the aorta. It is important to know the within patient variability of the transcranial motor evoked potential (tcMEP), before changes within the variability range are interpreted as abnormal during the period of aortic cross clamping. Lower limb muscle responses were obtained in 11 patients, following transcranial electrical stimulation with pulse trains, of 4, 6 and 8 pulses. Under the conditions of partial neuromuscular blockade and a stable low dose propofol/fentanyl/nitrous oxide anaesthetic state, this study shows that multipulse transcranial electrical stimulation reliably produces muscle responses of the lower limb in all patients tested with a coefficient of variation (CV) of around 20%. Eight pulses in the stimulation train produce neurophysiological facilitation that exceeds a 4 pulse train in terms of area under the curve (AUC) and response duration. The use of multipulse stimulation rather than double or single pulse stimulation is recommended in order to increase the clinical efficacy of tcMEP monitoring in aortic surgery.
From 1987 to 1991, over 36,000 men and women aged 20-59 years have been examined in the Monitoring Project on Cardiovascular Disease Risk Factors in The Netherlands. Classification of the treatment status of hypertensives in this population-based study was based on self-administered questionnaires. In order to assess the accuracy of self-reported antihypertensive drug use we compared the questionnaire information with computerized pharmacy records from a sample of 372 hypertensive subjects. Most antihypertensive drugs that were mentioned in the questionnaire were present in the pharmacy medication history (93%). However, this percentage was less (76%) when a comparison was made with the calculated duration of use based on the number of units prescribed and the directions for use in the pharmacy records. About 94% of the hypertensive subjects who were using an antihypertensive drug according to the pharmacy records, also mentioned at least one antihypertensive drug in the questionnaire. Agreement between self-reported antihypertensive drug use and pharmacy records was consistently high for all classes of antihypertensive drugs. Among 321 (86%) subjects, the number and types of self-reported antihypertensive drugs were exactly the same as in the pharmacy records. In conclusion, the agreement between self-reported antihypertensive drug use and pharmacy records was high, and the self-reported questionnaire information on antihypertensive drug use can be reliably used for the classification of treatment status of hypertensive subjects in this population-based study.
Intraoperative recording of myogenic motor potentials evoked by transcranial electrical stimulation (tcMEP) is a method of monitoring the integrity of the vulnerable motor pathways during thoracoabdominal aortic aneurysm (TAAA) surgery. Deflation of the left lung during TAAA surgery may result in impairment of arterial oxygenation. Ventilation with nitrous oxide may cause further desaturation. We studied the effects of 20%, 40% and 60% nitrous oxide in oxygen on within-patient variability and magnitude of tcMEP in response to six pulse transcranial electrical stimulation during fentanyl-low-dose propofol anaesthesia with partial neuromuscular block. Ten patients (two females; aged 63-74 yr) were studied. After achieving a stable anaesthetic state and before surgery, 10 tcMEP were recorded from the right tibialis anterior muscle during addition of 20%, 40% and 60% nitrous oxide in oxygen in random order. When ventilation with 40% or 60% nitrous oxide in oxygen was performed, there was 50-70% depression of tcMEP amplitude (P < 0.05) and 40-60% reduction in tcMEP area under the curve (P < 0.05) compared with 20% nitrous oxide in oxygen. There was no significant difference in the coefficients of variation for tcMEP between the three nitrous oxide anaesthetic regimens. Our results suggest that increasing doses of nitrous oxide reduce the MEP waveform to six pulse transcranial electrical stimulation, but even with 60% nitrous oxide in oxygen, the tcMEP were recordable and as reproducible as with 20% and 40% nitrous oxide regimens. The method is sufficiently robust for use in aortic surgery.
UNLABELLED: Intraoperative recording of myogenic motor responses evoked by transcranial electrical stimulation (tcMEPs) is a method of assessing the integrity of the motor pathways during aortic surgery. To identify conditions for optimal spinal cord monitoring, we investigated the effects of manipulating the level of neuromuscular blockade (T1 response of the train-of-four (TOF) stimulation 5%-15% versus T1 response 45%-55% of baseline), as well as the number of transcranial pulses (two versus six stimuli) on the within-patient variability and amplitude of tcMEPs. Ten patients (30-76 yr) scheduled to undergo surgery on the thoracic and thoracoabdominal aorta were studied. After achieving a stable anesthetic state and before surgery, 10 tcMEPs were recorded from the right extensor digitorum communis muscle and the right tibialis anterior muscle in response to two-pulse and six-pulse transcranial electrical stimulation with an interstimulus interval of 2 ms during two levels of neuromuscular blockade. The right thenar eminence was used for recording the level of relaxation. The tcMEP amplitude using the six-pulse paradigm was larger (P < 0.01; leg and arm) compared with the amplitude evoked by two-pulse stimulation during both levels of relaxation. The within-patient variability, expressed as median coefficient of variation, was less when six-pulse stimulation was used. At a T1 response of 45%-55% of baseline, larger, less variable tcMEPs were recorded than at a T1 response of 5%-15%. Our results suggest that the best quality of tcMEP signals (tibialis anterior muscle) is obtained when the six-pulse paradigm is used with a stable level of muscle relaxation (the first twitch of the TOF-thenar eminence-at 45%-55% of baseline). IMPLICATIONS: This study shows that six-pulse (rather than two-pulse) transcranial electrical stimulation during a stable anesthetic state and a stable neuromuscular blockade aimed at 45%-55% (rather than 5%-15%) of baseline provides reliable and recordable muscle responses sufficiently robust for spinal cord monitoring in aortic surgery.
In a study investigating the prevalence of underprescription of platelet therapy for women with angina pectoris, the complete medication histories of patients were examined and indicators of possible comorbidity and comedication were recorded. A higher percentage of women than men were not treated with any form of antithrombotic treatment (37% versus 18%), suggesting a serious, and possibly hazardous, undertreatment with acetylsalicylic acid (ASA) in women compared with men.
OBJECTIVE: To update mortality rates and long-term survival of patients admitted to the hospital with ruptured abdominal aortic aneurysm (AAA) and to study prognostic factors associated with mortality. DESIGN: Retrospective follow-up. MATERIALS: 309 patients (274 men, 35 women, average age 71) admitted to the hospital between January 1980 and January 1994 who were surgically treated for ruptured AAA were studied. METHODS: To identify the preoperative (9), intraoperative (23) and postoperative (49) variables associated with mortality logistic regression analysis (mortality within 48 h) and Cox regression analysis (mortality between 48 h and 30 days) were performed. RESULTS: Hospital mortality improved from 1980 to 1994. Compared with the normal population adjusted for age and sex the long-term mortality rate was increased (standardised mortality ratio 2.1; 95% confidence interval 1.7-2.5). Increased age, peroperative hypotension and need for a bifurcated graft were associated with significantly increased mortality. Co-morbidity was not a predictive variable. Overall hospital mortality was 25%. CONCLUSION: Surgical repair of ruptured AAA should be considered even in patients with co-morbidity. Elderly patients with severe preoperative hypotension have a very high mortality rate and surgery may not be justified in these cases. Long-term survival is also worse in older patients.
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OBJECTIVE: To estimate the level of undertreatment of hypertension in a population-based study by taking into account the co-existence of additional cardiovascular risk factors in untreated hypertensives, uncontrolled blood pressure among pharmacologically treated hypertensives and within-person variability in blood pressure and total cholesterol. DESIGN: Cross-sectional. SETTING: Two population-based surveys on cardiovascular disease risk factors conducted during 1987-1995 in The Netherlands. PARTICIPANTS: 56 026 men and women aged 20-59 years. MAIN OUTCOME MEASURES: Prevalence of hypertension, of treatment and of undertreatment of hypertension. Undertreated hypertensives were those who were treated pharmacologically, but whose blood pressure was still elevated and those who inappropriately received no medication for the treatment of hypertension. RESULTS: During the past decade in The Netherlands, 30% of the hypertensive women and 47% of the hypertensive men aged 20-59 years were undertreated for hypertension. In both men and women treated pharmacologically, 42 and 29%, respectively, still had elevated blood pressure levels. Of those hypertensive men and women not treated pharmacologically, 53 and 34%, respectively, should have been treated when additional cardiovascular risk factors were taken into account Among those diagnosed but untreated for hypertension, 58 and 31% of the men and women, respectively, should have been treated pharmacologically. CONCLUSION: A considerable proportion of hypertensives were undertreated for hypertension. To decrease the undertreatment of hypertension, it is necessary to obtain better control of blood pressure in patients already being treated, increase the detection of hypertension and improve adherence to the current guidelines.
OBJECTIVE: To describe and explain sex differences in antihypertensive drug use. DESIGN AND METHODS: From 1987 to 1995, two cross-sectional population-based surveys of cardiovascular disease risk factors in The Netherlands were carried out among 56026 men and women aged 20-59 years. Polytomous logistic regression modelling was used to adjust for potential confounders of the association between sex and use of different antihypertensive drugs. RESULTS: The response rate was 40% for men and 46% for women. Of these respondents, 40% (1041) of the hypertensive men and 59% (1403) of the hypertensive women were being treated pharmacologically; 57% (595) of the treated men and 54% (760) of the treated women were on monotherapy for hypertension with a diuretic (men 14.8%, women 37.2%), a beta-blocker (men 59.0%, women 45.3%), a calcium antagonist (men 8.6%, women 5.0%) or an angiotensin converting enzyme inhibitor (men 17.7%, women 12.5%). Among those on monotherapy for hypertension, women were less likely than men to be using a beta-blocker [prevalence odds ratio (POR), female/male=0.34; 95% confidence interval (CI) 0.24-0.47], a calcium antagonist (POR=0.27, 95% CI 0.15-0.48) or an angiotensin converting enzyme inhibitor (POR=0.34, 95% CI 0.22-0.52) than a diuretic. These sex differences persisted after adjustment for all factors that could have influenced the choice of these antihypertensive drugs (indications and contra-indications for the four antihypertensive drug classes). The sex differences in antihypertensive drug use were smaller among hypertensives with a history of cardiovascular disease (adjusted PORs, female/male, for beta-blockers, calcium antagonists and ACE inhibitors, respectively, compared to diuretics were 0.80 with 95% CI 0.20-3.24, 0.40 with 95% CI 0.10-0.48 and 0.64 with 95% CI 0.12-3.39) than among those without such a history. CONCLUSIONS: The different patterns of antihypertensive drug use among hypertensive men and women seem irrational, and cannot be explained by factors known to influence antihypertensive drug choice. Among hypertensives with a history of cardiovascular disease, the sex differences were smaller than among those without such a history. Further research is required to explain the sex differences in the choice of antihypertensive drug by prescribers, and to investigate the consequences of these differences for long-term patient outcomes.
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The validity of drug exposure measurement based on pharmacy records was investigated taking into account completeness of data, drug compliance, and different methods of drug exposure measurement in pharmacy records. Data on prescription drug use were collected from home inventories and community pharmacies in a survey on drug use and compliance in 115 elderly people. To compare drug exposure in pharmacy records with exposure in the home inventory, three different methods for exposure measurement in pharmacy records were used. Two employed a fixed time window of 30 and 90 days, respectively, and the third method was based on the calculated duration of use of a prescription ("legend time"). Drug exposure in the home inventory was taken as the gold standard and sensitivity, specificity, and positive predictive values of the different methods were calculated for the most frequently used drugs and drug categories. The specificity and positive predictive value of all three methods was generally high (0.93-1.00 and 0.67-1.00, respectively). The 90-day fixed method and the legend time method generally showed high sensitivity (range: 0.67-1.00 and 0.63-0.83, respectively) for drugs that were used on a chronic basis, while the 30-day fixed method had poor sensitivity (range: 0.29-0.69). Drugs that were used according to the home inventory but not according to the pharmacy records methods could be almost completely retrieved in the pharmacy records of a one-year period showing that these records were virtually complete with regard to prescription drugs. We conclude that computerized pharmacy records can be a reliable source of the true drug exposure as estimated in a home inventory, when adequate attention is paid to the definition of the exposure time-window and when these records are comprehensive with regard to prescription drugs.