Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma.

The possible influence of phenobarbital and phenytoin treatment on cancer risk was investigated in a case-control study nested in a cohort of 8004 epileptic patients in Denmark. Information on anticonvulsive treatments was abstracted for 95% of 60 patients with cancers of the liver and biliary tract or malignant lymphoma and for 94% of 171 cancer-free control patients. Use of anticonvulsive drugs was correlated with angiographic procedures that used Thorotrast, a well-known human liver carcinogen. After exclusion of study subjects exposed to Thorotrast, no association was seen between treatment with phenobarbital and cancer of the liver (odds ratio, 1.0; 95% confidence interval, 0.1-8.0) or biliary tract (odds ratio, 0.8; 95% confidence interval, 0.1-4.2). Furthermore, a histopathological evaluation of slides from 7 of 9 liver cancer patients not treated with Thorotrast revealed that 3 of the 4 cases of hepatocellular carcinoma involved cirrhosis of the liver, which suggested an etiological role for alcohol or viral hepatitis. A possible link was observed between use of phenytoin and risk for non-Hodgkin's lymphoma (1.8; 0.5-6.6), with a rising trend in risk with increasing dose. Our results suggest that the increased risk for cancers of the liver and biliary tract among Danish epileptic patients is likely to be due to Thorotrast administration and factors associated with cirrhosis of the liver rather than to anticonvulsive treatment.

Phenobarbital, drug metabolism, and human cancer.

To investigate the possible influence of anticonvulsant treatment on cancer risk, a nested case-control study of 104 lung cancers, 18 bladder cancers, and 322 cancer-free controls was conducted. The background for the study was previous observations among 8004 epileptics in Denmark with a significantly high risk for lung cancer and a significantly low risk for bladder cancer. Cigarette smoking appears to explain the lung cancer excess but not the low risk for bladder cancer, another tobacco-related disease. Information was abstracted on 94 and 95% of the cases and controls, respectively. Lung cancer was not associated with any anticonvulsant drug, but bladder cancer was inversely related to use of phenobarbital (PB). The apparent protective effect of PB was further evaluated in a study of rats given 4-aminobiphenyl (ABP), a bladder carcinogen. The levels of 4-aminobiphenyl adducts in hemoglobin and in bladder and liver DNA were significantly lower in rats given PB prior to 4-aminobiphenyl, compared to controls. These studies suggest that PB may induce drug-metabolizing enzymes of the liver that deactivate bladder carcinogens found in cigarette smoke and provide clues to the role of activation and detoxification of carcinogens in humans.

Magnetic fields and childhood cancer--a pooled analysis of two Scandinavian studies.

To test the hypothesis that exposure to magnetic fields, of the type generated by high voltage installations, increases cancer incidence in children, the original data from two case-control studies were pooled. The Swedish study was based on children living within 300 m from transmission lines, and the Danish study on the total population of Denmark. In both these studies, national cancer registries were used to identify cases of leukaemia, lymphoma or central nervous system tumour. Controls were selected randomly from the study populations. Magnetic field exposure was assessed through theoretical calculations of the magnetic fields before the time of diagnosis. An elevated relative risk of childhood leukaemia was found for calculated magnetic field levels of > or = 0.2 microT, estimated at 2.0 (95% CI 1.0-4.1), and for magnetic field levels of > or = 0.5 microT, estimated at 5.1 (95% CI 2.1-12.6). The results support the hypothesis of an association between magnetic fields and childhood leukaemia.

Parental employment at time of conception and risk of cancer in offspring.

Studies on the possible association between exposures of parents at the time off conception and cancer in their offspring have provided no clear answer. In this large, population-based, record-linkage study, 1747 childhood cancer cases were identified in the Danish Cancer Registry and matched with 8630 population controls. Specific information on the employment held by each parent at the time of conception and during early pregnancy was obtained through record linkages. The most recent job titles of the parents were also supplied. Significantly increased risks for renal cancer (mainly Wilms' tumour) and for osteogenic and soft tissue sarcomas were observed in children in association with mothers' employment in medical and dental care, based on 15 observations and odds ratios (OR) of 2.5-4.0. The risk for cancers at all sites was significantly elevated in children of female nurses (OR = 1.4; n = 75) and of male and female physicians, dentists, dental assistants, veterinarians and pharmacists combined (OR = 1.4; n = 53). Handling of drugs, exposure to anaesthetics and infections during pregnancy are suggested to be potential risk factors. Significantly increased risks were also observed for children of fathers employed in the manufacture of iron and metal structures (OR = 2.2; n = 16), in machine repair workshops (OR = 2.8; n = 6), as machinists (OR = 1.6; n = 47) and as smiths (OR = 1.5; n = 28). The suggestion in earlier studies that exposures to hydrocarbons and lead are risk factors for childhood cancer could not be supported by our analysis. Overall, few associations were observed; it was therefore concluded that parental occupation is not likely to be a major risk factor for childhood cancer.

Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer.

Data derived from experimental studies suggest that alpha-linolenic acid may have a protective effect in breast cancer. Observations obtained from epidemiological studies have not allowed conclusions to be drawn about a potential protective effect of dietary alpha-linolenic acid on breast cancer, possibly because of methodological issues. This case-control study conducted in an homogeneous population from a central area in France was designed to explore the hypothesis that alpha-linolenic acid inhibits breast cancer, using fatty acid levels in adipose breast tissue as a biomarker of past qualitative dietary intake of fatty acids. Biopsies of adipose breast tissue at the time of diagnosis were obtained from 123 women with invasive non-metastatic breast carcinoma. 59 women with benign breast disease served as controls. Individual fatty acids were analysed by capillary gas chromatography. An unconditional logistic regression model was used to obtain odds ratio estimates whilst adjusting for age, menopausal status and body mass index (BMI). No association was found between fatty acids (saturates, monounsaturates, long-chain polyunsaturates n-6 or n-3) and the disease, except for alpha-linolenic acid which showed an inverse association with the risk of breast cancer. The relative risk of breast cancer for women in the highest quartile of adipose breast tissue alpha-linolenic acid level was 0.36 (95% confidence interval=0.12-1.02) compared with those in the lowest quartile (P trend=0.026), suggesting a protective effect of alpha-linolenic acid in the risk of breast cancer. The effects of dietary alpha-linolenic on the risk of breast cancer warrant further study.

Incidence of pneumonia in mechanically ventilated patients treated with sucralfate or cimetidine as prophylaxis for stress bleeding: bacterial colonization of the stomach.

Retrograde colonization of the oropharynx from the stomach by microaspiration of gastric fluid is a recently recognized phenomenon associated with increased gastric pH that may result in pneumonia during ventilation therapy. In a prospective study we investigated 104 mechanically ventilated patients in the intensive care unit who were receiving sucralfate (n = 49) or cimetidine (n = 55) for stress ulcer prophylaxis. The incidence of pneumonia was 45.5% (25 patients) in the cimetidine group and 26.5% (13 patients) in the sucralfate group (95% confidence interval 0.98 to 6.97; odds ratio 2.61; p = 0.0549). Mortality rates were 18.4% (9 patients) in the sucralfate group versus 25.5% (14 patients) in the cimetidine group (p = 0.48). The mean pH values of gastric aspirates were significantly lower in patients treated with sucralfate than in patients receiving cimetidine (p = 0.044). The number of colony-forming units of Enterobacteriaceae in gastric aspirates was also significantly lower in the sucralfate group (p = 0.0037).

Estimation of extra hospital stay attributable to nosocomial infections: heterogeneity and timing of events.

Infections acquired in hospital are likely to affect the duration of hospitalization. Suitable statistical methods for estimating the extra days spent in hospital due to nosocomial infections should allow modeling of the heterogeneity of the patient population and the timing of events, as failure to account for important covariates and failure to model adequately the timing of events may lead to biased results. Three approaches have been used in the past to estimate the extra stay: a comparison of duration of stay of infected and uninfected patients, matching of infected and uninfected patients with respect to potentially important determinants of the length of hospital stay, and matching for time-to-infection in addition to the other factors. While these approaches can allow for the heterogeneity of the patient population, none takes sufficient account of the real timing of events and may overestimate the effect of nosocomial infections. We explored the statistical methods available for analyzing time-to-event data and derived alternative methods to estimate the extra stay that appropriately account for heterogeneity and timing. Data from two prospective cohort studies on postoperative wound infection and on nosocomial pneumonia showed that the two-group comparison yields the highest estimates of extra stay (21 and 14 extra days), while matching for confounders and time reduced the estimates to 11 and 8 extra days; our methods yield even lower results (10-12 and 3-4 extra days).

Prevalence and risk factors for nosocomial lower respiratory tract infections in German hospitals.

The prevalence and risk factors for nosocomial lower respiratory tract infections (LRTI) in Germany were determined as part of a national survey on nosocomial infections. The study included 14,966 patients in 72 representatively selected hospitals with departments of general medicine, surgery, obstetrics, gynecology, and intensive care units (ICU). Surveillance was carried out by four previously validated medical doctors who strictly applied the CDC-criteria for diagnosis of nosocomial infections. The overall prevalence of hospital-acquired LRTI was 0.72% with the highest rate in hospitals with more than 600 beds (1.08%) and among the patients on intensive care units (9.00%). Ventilator-associated pneumonia rates were highest in patients on ICUs (13.27). Polytrauma, impaired consciousness, chronic airway disease, prior surgery, and cardiovascular disease were significantly related to the occurrence of nosocomial LRTI. P. aeruginosa was the predominant organism causing nosocomial LRTI. Nosocomial LRTI remain a problem mainly on ICUs. Patients at risk should be monitored with extra care.

Identifying outliers of antibiotic usage in prevalence studies on nosocomial infections.

OBJECTIVE: To investigate whether the correlation between patients' antibiotic treatment (yes/no) and patients' infections (yes/no) in each hospital department, described by Pearson's correlation coefficient (p) for binary data as a measure for adequate use of antibiotics, is an appropriate quality indicator. DESIGN: Comparison of the results of repeated prevalence studies in different hospitals with the data of a national prevalence study, comparing the hospital (p) and reference (pNIDEP[Nosokomiale Infektionen in Deutschland: Erfassung und Pravention]) correlation coefficients for "use of antibiotics/ presence of infections." SETTING: The data of 5,377 surgical patients were separated from the total data of a national prevalence study in 72 representative hospitals to create a reference correlation coefficient (rhoNIDEP) with a reference range. Nine additional prevalence studies, involving a total of 4,984 patients, were repeatedly performed in the surgical departments of 8 other hospitals during a 12-month period, whereby the correlation coefficients rho(n) for every prevalence investigation were determined. RESULTS: In the national prevalence study, 15.3% of the surgical patients received antibiotics on the study day. Surgical patients had a 3.8% prevalence of nosocomial infections and a 7.0% prevalence of community-acquired infections. Pearson's correlation coefficient rhoNIDEP for correlation between patients' binary data use of antibiotics and presence of infection was 0.62. To compare the correlation coefficient of each department with the appropriate reference range, the coefficients of the single departments were plotted against the number of patients; in these plots, three lines indicated the value rhoNIDEP and the upper and lower reference ranges, depending on the number of patients. Seven of eight surgical departments investigated during the repeated prevalence studies were found to be within the reference range, near the reference value, in the majority of prevalence studies; only one of the departments was identified as an outlier as regards antibiotic use. CONCLUSION: The correlation between patients' antibiotic treatment (yes/no) and patients' infections (yes/no) in hospitals or departments, as described by Pearson's correlation coefficient p for binary data with a definitive reference range depending on the number of patients, is useful for quality management in identifying the overall necessity for evaluating the indications for antibiotic use in one's own hospital.

Scoring system for nosocomial pneumonia in ICUs.

OBJECTIVE: To develop a scoring system for stratifying patients in intensive care units (ICUs) by risk of developing nosocomial pneumonia (NP), based on variables generally available in an ICU, and to determine the probability of a patient developing NO in the ICU. DESIGN AND SETTING: a 2-year prospective cohort study conducted in a medical and surgical ICU. PATIENTS: 756 patients admitted to the ICU for 48 h or more were followed up until the development of NP or death or discharge from the ICU. MEASUREMENTS AND RESULTS: 129 (17.1%) patients developed NP, 106 (14%) in the first 2 weeks. The following independent risk factors were identified by multivariate analysis: no infection on admission [relative risk (RR) = 3.1, 95% confidence intervals (CI) = 2.0 to 4.81; thorax drainage (RR = 2.1, 95% CI = 1.2 to 3.5); administration of antacids (RR = 2.1, 95% CI = 1.4 to 3.1); partial pressure of oxygen (PO2) > 110 mmHg (RR = 1.6, 95% CI = 1.0 to 2.6); administration of coagulation factors (RR = 1.8 95% CI = 1.0 to 3.2); male gender (RR = 2.7, 95% CI = 1.2 to 6.3); urgent surgery (RR = 2.4, 95% CI = 0.9 to 6.4); and neurological diseases (RR = 4.2, 95% CI = 1.9 to 9.4). To obtain a predictive risk index for NP, a scoring system was developed using a multivariate model. The probability of developing NP varied between 11.0% in the lowest risk group and 42.3% in the highest risk group. The patients' risk of acquiring NP was seven times higher in the highest score category (i.v.) than in the lowest one (I). CONCLUSIONS: ICU patients can be stratified into high- and low-risk groups for NP. No infection on admission, thorax drainage, administration of antacids, and PO2 > 110 mmHg were associated with a higher risk of NP during the entire 2-week period.

Prevalence of nosocomial infections in representative German hospitals.

The nosocomial infection (NI) rate in German hospitals was studied in order to create reference data for comparison in hospitals where ongoing surveillance is impossible. The study was designed as a one-day prevalence study. Patients in 72 selected hospitals (inclusion criteria: acute care hospitals with departments for general medicine, surgery, obstetrics/gynaecology) were examined by four external investigators (physicians trained and validated in the diagnosis of NI). A total of 14,996 patients were studied. The overall prevalence rate was 3.5% (CI 3.1-3.9) with a variation of 0-8.9% between hospitals. The commonest NI were: urinary tract infection (42.1%), lower respiratory tract infection (20.6%), surgical site infections (15.8%) and primary sepsis (8.3%). The highest prevalence rate (15.3%) was found in intensive care ward patients, followed by surgery (3.8%), general medicine (3.0%) and gynaecology/obstetrics (1.4%). The infection rate varied significantly with hospital size. A microbiology laboratory report was only available for 56.5% of patients thought to have an NI, and there were remarkable differences between hospitals with and without an on-site microbiology laboratory. Because of this and other methodological reasons the NI prevalence rates reported here may represent the absolute minimum of nosocomially infected patients in Germany.

Comparison of effectiveness and required time of two surveillance methods in intensive care patients.

The intensive care unit (ICU) standardized protocol of the NNIS (National Nosocomial Infections Surveillance) system is a surveillance method of hospital acquired infections (HAI), which provides device-associated infection rates. The aim of this study was to assess the effectiveness and the required time for data collection and analysis of a selective surveillance method (SSM) derived from the NNIS ICU surveillance protocol, and to compare its data with that of a reference surveillance method (RSM). The sensitivity, specificity and the positive predictive value (PPV) of the RSM were 87.5, 100 and 100%, respectively. The sensitivity, specificity and the PPV of the SSM were 59.4 97.6 and 79.2%, respectively. Considering device-related infections only (ventilator-related pneumonia, catheter-related urinary tract infections, central line-related sepsis), the sensitivities of the RSM and the SSM were 80.9 and 90.5%, respectively. The SSM required only one third of the time of the RSM (1.1 h and 3.4 h per 10 beds per week with the SSM and the RSM, respectively). We conclude that the SSM has a very high sensitivity for detecting device associated infections, but is not sensitive enough for surveying all types of HAI.

Modeling psychotherapy outcome as event in time: an application of multistate analysis.

Standard survival analysis (SA) and multistate analysis (MSA) are methods for modeling categorical psychotherapy outcome events over time. The underlying principles, mathematical details, and indications for using each technique are discussed, and data from an anorexia nervosa psychotherapy outcome study comparing psychodynamic psychotherapy with psychodynamic psychotherapy plus cognitive-behavioral techniques are used to illustrate the use of SA and MSA techniques. MSA includes multiple competing outcome states in a single model. A single MSA model includes reaching target weight and treatment dropout before reaching target weight as competing events. It is concluded that MSA is an informative analytic technique in the domain of psychotherapy research.

[Microbiological and economic studies of abbreviated procedures for surgical hand disinfection]. / Mikrobiologische und ökonomische Untersuchungen über verkürzte Verfahren für die chirurgische Händedesinfektion.

An investigation was performed of whether shortened procedures for surgical hand disinfection (2 and 3 min, respectively) are equally effective as the usual German standard procedure of 5 min duration and, in addition, which saving of working time and costs would be achievable if shorter procedures were employed. The shortened procedures were: 1) 3 min alcoholic disinfectant (1 min prior handwashing) and 2) 1 min chlorhexidine detergent (Hibiscrub), 2 min 0.5% chlorhexidine in 70% isopropanol (Hibisol). The two shortened procedures were equally effective as the standard procedure (test of equivalence, p < 0.05). The savings of working time and costs calculated for 17708 operations were 1) 2360 h or 79768 German marks and 2) 3540 h or 119652 German marks, respectively.

Residence near high voltage facilities and risk of cancer in children.

OBJECTIVE: To investigate whether residence before and after birth near 50 Hz high voltage installations increases a child's risk of cancer and whether risk correlates with the strength of the magnetic field. DESIGN: A population based case-control study. SETTING: Denmark. SUBJECTS: 1707 children under the age of 15 with leukaemia, tumour of the central nervous system, or malignant lymphoma diagnosed in 1968-86 and 4788 children taken from the central population register. MAIN OUTCOME MEASURES: Proximity before and after birth to existing or former 50-400 kV electrical transmission connections and substations and associated historical electromagnetic fields calculated on the basis of current load on line, phase ordering of line, and distance from the dwelling. RESULTS: A significant association was seen between all major types of childhood cancer combined and exposure to magnetic fields from high voltage installations of > or = 0.4 microT (odds ratio 5.6). At > or = 0.25 microT no significant association was seen (odds ratio 1.5). A possible association was also seen with cases of Hodgkin's disease separately at > or = 0.1 microT. CONCLUSIONS: On the basis these results and additional descriptive data on electricity consumption and incidence of childhood cancer in Denmark since the 1940s it was concluded that the proportion of childhood cancer possibly caused by 50 Hz electromagnetic fields must be small.

[Nosocomial infections in Germany. Microbiological diagnosis, preventive antibiotics and antibiotic therapy]. / Nosokomiale Infektionen in Deutschland (NIDEP). Mikrobiologische Diagnostik, Antibiotikaprophylaxe und Antibiotikatherapie.

BACKGROUND: The NIDEP-study (Nosocomial Infections in Germany-Prevalence and Prevention) is the first large multicenter survey to examine the prevalence of nosocomial infections (NI) in Germany. This part of the NIDEP-study describes the frequency and quality of the microbiological diagnosis, antimicrobial chemoprophylaxis and therapy in representative German hospitals. PATIENTS AND METHOD: Prevalence of nosocomial infections in 14 966 patients of 72 randomly selected representative German hospitals was determined. Frequency, nature and results of the microbiological diagnosis, antimicrobial chemoprophylaxis and therapy were recorded simultaneously. RESULTS: The total prevalence rate of nosocomial infections was 3.5%. The most common infections were urinary tract infections (42.1%), lower respiratory tract infections (20.6%), postoperative wound infections (15.8%), and septicemia (8.3%). Microbiological evaluation was done in 56.5% of the patients with infections. Only five of the 49 hospitals with less than 400 beds and only nine of the 23 hospitals with more than 400 beds had their own microbiological department. Antimicrobial chemotherapy was administered in 17.7% of the patients. In 35.1% of the patients who were treated with antibiotics, no clinical diagnosis of infection was made, criteria for nosocomial infections were not fulfilled or microbiological evaluation was not established. Antimicrobial chemoprophylaxis was done in one third of the patients. Prophylaxis was missed in 20.6% of patients with colorectal operations, 60.1% of appendectomies, 48% of vaginal hysterectomies, and 35.5% of total hip replacements. On the other hand antimicrobial chemoprophylaxis was frequently administered in clean procedures without increased risk of postoperative wound infections. CONCLUSION: Insufficient microbiological evaluation, inadequate perioperative antimicrobial chemoprophylaxis and administration of chemotherapy without documented infection were detected in representative German hospitals.

[Electromagnetic fields from high-voltage installations and cancer in childhood]. / Elektromagnetiske felter fra højspaendingsanlaeg og børnecancer.

The objective of this population-based case-control study has been to investigate whether residence before and after birth near 50 Hz high voltage installations increases a child's risk of cancer and whether risk correlates with the strength of the magnetic field. One thousand seven hundred and seven children under the age of 15 with either leukaemia, a tumour of the central nervous system, or malignant lymphoma diagnosed in 1968-86 were identified in the Danish Cancer Registry and matched with 4788 population controls. Measures of exposure were proximity before and after birth to existing or former 50-400 kV electrical transmission connections and substations and associated historical electromagnetic fields calculated on the basis of current load on line, phase ordering of line, and distance from the dwelling. A significant association was seen between all major types of childhood cancer combined and exposure to magnetic fields from high voltage installations of > or = 0.4 microT (odds ratio 5.6). At > or = 0.25 microT no significant association was seen (odds ratio 1.5). A possible association was also seen with cases of Hodgkin's disease separately at > or = 0.1 microT. On the basis of these results and additional descriptive data on electricity consumption and incidence of childhood cancer in Denmark since the 1940s it was concluded that the proportion of childhood cancer possibly caused by 50 Hz electromagnetic fields must be small.

A measure of similarity for response curves based on ranks.

A measure of similarity for response curves is presented and its potential use is discussed. The distribution of a suitable test statistic for testing the independence of the course of two curves is derived. The method proposed is compared with other proposals in the literature for the analysis of paired response curves. A study on the quality of life of patients with acute heart failure is used as an example.

Estimation of prolongation of hospital stay attributable to nosocomial infections: new approaches based on multistate models.

Evaluation of the impact of nosocomial infection on duration of hospital stay usually relies on estimates obtained in prospective cohort studies. However, the statistical methods used to estimate the extra length of stay are usually not adequate. A naive comparison of duration of stay in infected and non-infected patients is not adequate to estimate the extra hospitalisation time due to nosocomial infections. Matching for duration of stay prior to infection can compensate in part for the bias of ad hoc methods. New model-based approaches have been developed to estimate the excess length of stay. It will be demonstrated that statistical models based on multivariate counting processes provide an appropriate framework to analyse the occurrence and impact of nosocomial infections. We will propose and investigate new approaches to estimate the extra time spent in hospitals attributable to nosocomial infections based on functionals of the transition probabilities in multistate models. Additionally, within the class of structural nested failure time models an alternative approach to estimate the extra stay due to nosocomial infections is derived. The methods are illustrated using data from a cohort study on 756 patients admitted to intensive care units at the University Hospital in Freiburg.

Assessment of quality of life in clinical trials.

This paper is intended as an overview of developments in the assessment of quality of life (QOL) in clinical trials over the last decade from the viewpoint of clinical biostatistics. In the first part we deal with aspects of obtaining adequate measurements of quality of life. A literature survey shows that a large number of quite heterogeneous measurement approaches for use in clinical trials exist, a substantial percentage of which cannot be regarded as sufficient for their actual measuring purpose. In the second part we review statistical methods applied to and adapted for the analysis of QOL data. Underlying the analysis should be the assumption of QOL as a stochastic process. Applied analysis procedures are again investigated in a literature survey. Finally, critical conclusions are outlined and suggestions for further research are given.