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1.  Are Entry Criteria for Cataract Surgery Justified? 
PLoS ONE  2014;9(11):e112819.
The German Ophthalmological Society (GOS) recently proposed surgical entry criteria, i.e. 300 cataract surgeries. We herein correlate the surgical hands-on experience with the risk of posterior capsule ruptures in order to assess whether this number is appropriate.
We identified all cataract operations that had been performed at the University Eye Hospital Freiburg since 1995. For each surgeon, we assigned a running number to his/her procedures in the order they had been performed. Thereafter, we excluded all combined procedures and the second eyes. We then selected the 5475 surgical reports between November 2008 and November 2012 for detailed review. We additionally classified each surgery into low- vs. high- à priori risk for posterior capsule ruptures. We fitted a multifactorial logistic regression model to assess the GOS recommendation of 300 surgeries under supervision. In the low-risk group, we additionally visualized the 'typical' learning curve by plotting the posterior capsule ruptures against the respective rank numbers.
The odds ratio for posterior capsule ruptures of 'learning-mode' (one of the respective surgeon's 300 first procedures) vs. the non-learning-mode was 3.8 (p<0.0001). By contrast, classification into the low-risk group lowered the risk of posterior capsule ruptures three fold (p<0.0001). According to the low-risk plot, the surgeons started with a complication rate of 4% and continuously improved towards 0.5% after 1500 operations. Thereafter, the rate increased again and stabilized around one percent.
The learning curve with respect to posterior capsule ruptures is surprisingly flat. The GOS entry criterion of 300 cataract procedures is therefore most likely justified. Careful selection of low-risk patients for the training surgeons may help in reducing the rate of posterior capsule ruptures during training.
PMCID: PMC4234514  PMID: 25401738
2.  Choice of Non-Inferiority (NI) Margins Does Not Protect against Degradation of Treatment Effects on an Average – An Observational Study of Registered and Published NI Trials 
PLoS ONE  2014;9(7):e103616.
NI margins have to be chosen appropriately to control the risk of degradation of treatment effects in non-inferiority (NI) trials. We aimed to study whether the current choice of NI margins protects sufficiently against a degradation of treatment effect on an average.
Study Design and Setting
NI trials reflecting current practice were assembled and for each trial, the NI margin was translated into a likelihood of degradation. The likelihood of degradation was calculated as the conditional probability of a treatment being harmful given that it is declared non-inferior in the trial, using simulation. Its distribution among the NI trials was then studied to assess the potential risk of degradation.
The median (lower/upper quartile) NI margin among 112 binary outcome NI trials corresponded to an odds ratio of 0.57(0.45, 0.66), while among 38 NI trials with continuous outcome, to a Cohen’s d of −0.42(−0.54, −0.31) and a hazard ratio of 0.82(0.73, 0.86) among 24 survival outcome NI trials. Overall, the median likelihood of degradation was 56% (45%, 62%).
Only two fifths of the current NI trials had a likelihood of degradation lower than 50%, suggesting that, in majority of the NI trials, there is no sufficient protection against degradation on an average. We suggest a third hurdle for the choice of NI margins, thus contributing a sufficient degree of protection.
PMCID: PMC4117500  PMID: 25080093
3.  Feasibility and impact of an intensified antibiotic stewardship programme targeting cephalosporin and fluoroquinolone use in a tertiary care university medical center 
BMC Infectious Diseases  2014;14:201.
Restricted use of third-generation cephalosporins and fluoroquinolones has been linked to a reduced incidence of hospital-acquired infections with multidrug-resistant bacteria. We implemented an intensified antibiotic stewardship (ABS) programme in the medical service of a university hospital center aiming at a reduction by at least 30% in the use of these two drug classes.
The ABS programme was focused on the 300-bed medical service. Prescription of third-generation cephalosporins was discouraged, whereas the use of penicillins was encouraged. Monthly drug use density was measured in WHO-ATC defined and locally recommended daily doses (DDD and RDD) per 100 patient days, to evaluate trends before (01/2008 to 10/2011) and after starting the intervention (1/2012 to 3/2013). The effect was analysed using interrupted time-series analysis with six non-intervention departments as controls.
Following initiation of the ABS intervention, overall antibiotic use in the medical service declined (p < 0.001). There was a significant intervention-related decrease in the use of cephalosporins and fluoroquinolones (p < 0.001) outperforming the decreasing baseline trend. Trend changes observed in some of the control departments were smaller, and the difference between trend changes in the medical service and those in control departments were highly significant for overall use and cephalosporin use reductions (p < 0.001) as well as for the increasing use of penicillins (p < 0.001). Mean use density levels (in RDD per 100 patient days) dropped for cephalosporins from 16.3 to 10.3 (−37%) and for fluoroquinolones from 17.7 to 10.1 (−43%), respectively. During the same period, the use of penicillins increased (15.4 to 18.2; 18%). The changes in expenditures for antibiotics in the medical service compared to control services minus programme costs indicated initial net cost savings likely to be associated with the programme.
An intensified ABS programme targeting cephalosporin und fluoroquinolone use in the setting of a large academic hospital is feasible and effective. The intervention may serve as a model for other services and hospitals with a similar structure and baseline situation.
PMCID: PMC3999502  PMID: 24731220
Antibiotic stewardship; Interrupted time-series analysis; Cephalosporins; Fluoroquinolones
4.  Impact of availability of guidelines and active surveillance in reducing the incidence of ventilator-associated pneumonia in Europe and worldwide 
BMC Infectious Diseases  2014;14:199.
To analyse whether the availability of written standards for management of mechanically ventilated patients and/or the existence of a surveillance system for cases of ventilation-associated pneumonia (VAP) are positively associated with compliance with 6 well-established VAP prevention measures.
Ecological study based on responses to an online-questionnaire completed by 1730 critical care physicians. Replies were received from 77 different countries, of which the majority, i.e. 1351, came from 36 European countries.
On a cross-country level, compliance with VAP prevention measures is higher in countries with a large number of prevention standards and/or VAP surveillance systems in place at ICU level., Likewise, implementation of standards and VAP surveillance systems has a significant impact on self-reported total compliance with VAP prevention measures (both p < 0.001). Moreover, predictions of overall prevention measure compliance show the effect size of the availability of written standards and existence of surveillance system. For instance, a female physician with 10 years of experience in critical care working in a 15-bed ICU in France has a predicted baseline level of VAP prevention measure compliance of 63 per cent. This baseline level increases by 9.5 percentage points (p < 0.001) if a written clinical VAP prevention standard is available in the ICU, and by another 4 percentage points (p < 0.001) if complemented by a VAP surveillance system.
The existence of written standards for management of mechanically ventilated patients in an ICU and the availability of VAP surveillance systems have shown to be positively associated with compliance with VAP prevention measures and should be fostered on a policy level.
PMCID: PMC4021349  PMID: 24725914
Ventilation-associated pneumonia; VAP; Bundle; Guideline; Surveillance
5.  Game-Based E-Learning Is More Effective than a Conventional Instructional Method: A Randomized Controlled Trial with Third-Year Medical Students 
PLoS ONE  2013;8(12):e82328.
When compared with more traditional instructional methods, Game-based e-learning (GbEl) promises a higher motivation of learners by presenting contents in an interactive, rule-based and competitive way. Most recent systematic reviews and meta-analysis of studies on Game-based learning and GbEl in the medical professions have shown limited effects of these instructional methods.
To compare the effectiveness on the learning outcome of a Game-based e-learning (GbEl) instruction with a conventional script-based instruction in the teaching of phase contrast microscopy urinalysis under routine training conditions of undergraduate medical students.
A randomized controlled trial was conducted with 145 medical students in their third year of training in the Department of Urology at the University Medical Center Freiburg, Germany. 82 subjects where allocated for training with an educational adventure-game (GbEl group) and 69 subjects for conventional training with a written script-based approach (script group). Learning outcome was measured with a 34 item single choice test. Students' attitudes were collected by a questionnaire regarding fun with the training, motivation to continue the training and self-assessment of acquired knowledge.
The students in the GbEl group achieved significantly better results in the cognitive knowledge test than the students in the script group: the mean score was 28.6 for the GbEl group and 26.0 for the script group of a total of 34.0 points with a Cohen's d effect size of 0.71 (ITT analysis). Attitudes towards the recent learning experience were significantly more positive with GbEl. Students reported to have more fun while learning with the game when compared to the script-based approach.
Game-based e-learning is more effective than a script-based approach for the training of urinalysis in regard to cognitive learning outcome and has a high positive motivational impact on learning. Game-based e-learning can be used as an effective teaching method for self-instruction.
PMCID: PMC3857775  PMID: 24349257
6.  Potential role of “the compensating benefit” in claiming non-inferiority 
Trials  2013;14(Suppl 1):P12.
PMCID: PMC3980833
9.  Google Scholar as replacement for systematic literature searches: good relative recall and precision are not enough 
Recent research indicates a high recall in Google Scholar searches for systematic reviews. These reports raised high expectations of Google Scholar as a unified and easy to use search interface. However, studies on the coverage of Google Scholar rarely used the search interface in a realistic approach but instead merely checked for the existence of gold standard references. In addition, the severe limitations of the Google Search interface must be taken into consideration when comparing with professional literature retrieval tools.
The objectives of this work are to measure the relative recall and precision of searches with Google Scholar under conditions which are derived from structured search procedures conventional in scientific literature retrieval; and to provide an overview of current advantages and disadvantages of the Google Scholar search interface in scientific literature retrieval.
General and MEDLINE-specific search strategies were retrieved from 14 Cochrane systematic reviews. Cochrane systematic review search strategies were translated to Google Scholar search expression as good as possible under consideration of the original search semantics. The references of the included studies from the Cochrane reviews were checked for their inclusion in the result sets of the Google Scholar searches. Relative recall and precision were calculated.
We investigated Cochrane reviews with a number of included references between 11 and 70 with a total of 396 references. The Google Scholar searches resulted in sets between 4,320 and 67,800 and a total of 291,190 hits. The relative recall of the Google Scholar searches had a minimum of 76.2% and a maximum of 100% (7 searches). The precision of the Google Scholar searches had a minimum of 0.05% and a maximum of 0.92%. The overall relative recall for all searches was 92.9%, the overall precision was 0.13%.
The reported relative recall must be interpreted with care. It is a quality indicator of Google Scholar confined to an experimental setting which is unavailable in systematic retrieval due to the severe limitations of the Google Scholar search interface. Currently, Google Scholar does not provide necessary elements for systematic scientific literature retrieval such as tools for incremental query optimization, export of a large number of references, a visual search builder or a history function. Google Scholar is not ready as a professional searching tool for tasks where structured retrieval methodology is necessary.
PMCID: PMC3840556  PMID: 24160679
Literature search; Literature search; Methods; Literature search; Systematic; Information storage and retrieval; Google Scholar; Medline
10.  Shared decision-making in antihypertensive therapy: a cluster randomised controlled trial 
BMC Family Practice  2013;14:135.
Hypertension is one of the key factors causing cardiovascular diseases. A substantial proportion of treated hypertensive patients do not reach recommended target blood pressure values. Shared decision making (SDM) is to enhance the active role of patients. As until now there exists little information on the effects of SDM training in antihypertensive therapy, we tested the effect of an SDM training programme for general practitioners (GPs). Our hypotheses are that this SDM training (1) enhances the participation of patients and (2) leads to an enhanced decrease in blood pressure (BP) values, compared to patients receiving usual care without prior SDM training for GPs.
The study was conducted as a cluster randomised controlled trial (cRCT) with GP practices in Southwest Germany. Each GP practice included patients with treated but uncontrolled hypertension and/or with relevant comorbidity. After baseline assessment (T0) GP practices were randomly allocated into an intervention and a control arm. GPs of the intervention group took part in the SDM training. GPs of the control group treated their patients as usual. The intervention was blinded to the patients. Primary endpoints on patient level were (1) change of patients’ perceived participation (SDM-Q-9) and (2) change of systolic BP (24h-mean). Secondary endpoints were changes of (1) diastolic BP (24h-mean), (2) patients’ knowledge about hypertension, (3) adherence (MARS-D), and (4) cardiovascular risk score (CVR).
In total 1357 patients from 36 general practices were screened for blood pressure control by ambulatory blood pressure monitoring (ABPM). Thereof 1120 patients remained in the study because of uncontrolled (but treated) hypertension and/or a relevant comorbidity. At T0 the intervention group involved 17 GP practices with 552 patients and the control group 19 GP practices with 568 patients. The effectiveness analysis could not demonstrate a significant or relevant effect of the SDM training on any of the endpoints.
The study hypothesis that the SDM training enhanced patients’ perceived participation and lowered their BP could not be confirmed. Further research is needed to examine the impact of patient participation on the treatment of hypertension in primary care.
Trial registration
German Clinical Trials Register (DRKS): DRKS00000125
PMCID: PMC3847233  PMID: 24024587
Hypertension; Shared decision-making; Ambulatory blood pressure monitoring; Educational training; Primary care; Family medicine; Cluster randomised controlled trial
11.  Earliest Evidence for Social Endogamy in the 9,000-Year-Old-Population of Basta, Jordan 
PLoS ONE  2013;8(6):e65649.
The transition from mobile to sedentary life was one of the greatest social challenges of the human past. Yet little is known about the impact of this fundamental change on social interactions amongst early Neolithic communities, which are best recorded in the Near East. The importance of social processes associated with these economic and ecological changes has long been underestimated. However, ethnographic observations demonstrate that generalized reciprocity – such as open access to resources and land – had to be reduced to a circumscribed group before regular farming and herding could be successfully established. Our aim was thus to investigate the role of familial relationships as one possible factor within this process of segregation as recorded directly in the skeletal remains, rather than based on hypothetical correlations such as house types and social units. Here we present the revealing results of the systematically recorded epigenetic characteristics of teeth and skulls of the late Pre-Pottery Neolithic community of Basta in Southern Jordan (Figure S1). Additionally, mobility was reconstructed via a systematic strontium (Sr) isotope analysis of tooth enamel of the Basta individuals. The frequency of congenitally missing maxillary lateral incisors in the 9,000-year-old community of Basta is exceptionally high (35.7%). Genetic studies and a worldwide comparison of the general rate of this dental anomaly in modern and historic populations show that the enhanced frequency can only be explained by close familial relationships akin to endogamy. This is supported by strontium isotope analyses of teeth, indicating a local origin of almost all investigated individuals. Yet, the accompanying archaeological finds document far-reaching economic exchange with neighboring groups and a population density hitherto unparalleled. We thus conclude that endogamy in the early Neolithic village of Basta was not due to geographic isolation or a lack of exogamous mating partners but a socio-cultural choice.
PMCID: PMC3679157  PMID: 23776517
12.  Gene Expression Signatures That Predict Outcome of Tamoxifen-Treated Estrogen Receptor-Positive, High-Risk, Primary Breast Cancer Patients: A DBCG Study 
PLoS ONE  2013;8(1):e54078.
Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy.
Methodology/Principal Findings
Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25).
A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential.
PMCID: PMC3546921  PMID: 23342080
13.  Reproducibility of range of motion and muscle strength measurements in patients with hip osteoarthritis – an inter-rater study 
Assessment of range of motion (ROM) and muscle strength is fundamental in the clinical diagnosis of hip osteoarthritis (OA) but reproducibility of these measurements has mostly involved clinicians from secondary care and has rarely reported agreement parameters. Therefore, the primary objective of the study was to determine the inter-rater reproducibility of ROM and muscle strength measurements. Furthermore, the reliability of the overall assessment of clinical hip OA was evaluated. Reporting is in accordance with proposed guidelines for the reporting of reliability and agreement studies (GRRAS).
In a university hospital, four blinded raters independently examined patients with unilateral hip OA; two hospital orthopaedists independently examined 48 (24 men) patients and two primary care chiropractors examined 61 patients (29 men). ROM was measured in degrees (deg.) with a standard two-arm goniometer and muscle strength in Newton (N) using a hand-held dynamometer. Reproducibility is reported as agreement and reliability between paired raters of the same profession. Agreement is reported as limits of agreement (LoA) and reliability is reported with intraclass correlation coefficients (ICC). Reliability of the overall assessment of clinical OA is reported as weighted kappa.
Between orthopaedists, agreement for ROM ranged from LoA [-28–12 deg.] for internal rotation to [-8–13 deg.] for extension. ICC ranged between 0.53 and 0.73, highest for flexion. For muscle strength between orthopaedists, LoA ranged from [-65–47N] for external rotation to [-10 –59N] for flexion. ICC ranged between 0.52 and 0.85, highest for abduction. Between chiropractors, agreement for ROM ranged from LoA [-25–30 deg.] for internal rotation to [-13–21 deg.] for flexion. ICC ranged between 0.14 and 0.79, highest for flexion. For muscle strength between chiropractors, LoA ranged between [-80–20N] for external rotation to [-146–55N] for abduction. ICC ranged between 0.38 and 0.81, highest for flexion. Weighted kappa for the overall assessment of clinical hip OA was 0.52 between orthopaedists and 0.65 between chiropractors.
Reproducibility of goniometric and dynamometric measurements of ROM and muscle strength in patients with hip OA is poor between experienced orthopaedists and between experienced chiropractors. Orthopaedists and chiropractors can to a moderate degree differentiate between hips with or without osteoarthritis.
PMCID: PMC3565957  PMID: 23217149
Hip; Examination; Inter-observer; Reliability; Osteoarthritis; Hip
14.  Implementation of shared decision making by physician training to optimise hypertension treatment. Study protocol of a cluster-RCT 
Hypertension is one of the key factors causing cardiovascular diseases which make up the most frequent cause of death in industrialised nations. However about 60% of hypertensive patients in Germany treated with antihypertensives do not reach the recommended target blood pressure. The involvement of patients in medical decision making fulfils not only an ethical imperative but, furthermore, has the potential of higher treatment success. One concept to enhance the active role of patients is shared decision making. Until now there exists little information on the effects of shared decision making trainings for general practitioners on patient participation and on lowering blood pressure in hypertensive patients.
In a cluster-randomised controlled trial 1800 patients receiving antihypertensives will be screened with 24 h ambulatory blood pressure monitoring in their general practitioners’ practices. Only patients who have not reached their blood pressure target (approximately 1200) will remain in the study (T1 – T3). General practitioners of the intervention group will take part in a shared decision making-training after baseline assessment (T0). General practitioners of the control group will treat their patients as usual. Primary endpoints are change of systolic blood pressure and change of patients’ perceived participation. Secondary endpoints are changes of diastolic blood pressure, knowledge, medical adherence and cardiovascular risk. Data analysis will be performed with mixed effects models.
The hypothesis underlying this study is that shared decision making, realised by a shared decision making training for general practitioners, activates patients, facilitates patients’ empowerment and contributes to a better hypertension control. This study is the first one that tests this hypothesis with a (cluster-) randomised trial and a large sample size.
Trial registration
WHO International Clinical Trials:
PMCID: PMC3467178  PMID: 22966894
Arterial hypertension; Cardiovascular diseases; Cardiovascular risk; Shared decision making; Educational training; Blood pressure control; Ambulatory blood pressure monitoring; Adherence; Primary care; Family medicine
15.  Interim analyses in diagnostic versus treatment studies: differences and similarities 
The purpose of this paper was to contrast interim analyses in (randomized controlled) treatment studies with interim analyses in paired diagnostic studies of accuracy with respect to planning and conduct. The term ‘treatment study’ refers to a (randomized) clinical trial that aims to demonstrate the superiority or noninferiority of one treatment compared with another, and the term ‘diagnostic study’ to a clinical study that compares two diagnostic procedures, using a third diagnostic procedure as the gold standard. Though interim analyses in treatment studies and paired diagnostic studies show similarities in a priori planning of timing, decision rules, and the consequences of the analyses, they differ with respect to (1) the need for sample size adjustments, (2) the possibility of early decisions without early stopping, and (3) the impact of keeping results secret. These differences are due, respectively, to certain characteristics of paired diagnostic studies: the dependence of the sample size on the agreement rate between the modalities, multiple aims of diagnostic accuracy studies, and the advantages of early unblinding of results at the individual level. We exemplified our points by using a recent investigation at our institution on the detection of bone metastases from prostate cancer in patients with histologically confirmed prostate cancer in which 99mTc-MDP whole body bone scintigraphy was compared to positron emission tomography/computed tomography with 18F-fluorocholine as tracer, using magnetic resonance imaging as a reference.
PMCID: PMC3477734  PMID: 23133821
Study design; diagnostic imaging; PET/CT; efficacy studies; accuracy studies; sample size
16.  Is there a danger of “biocreep” with non-inferiority trials? 
Trials  2011;12(Suppl 1):A29.
PMCID: PMC3287743
17.  How to study optimal timing of PET/CT for monitoring of cancer treatment 
The use of PET/CT for monitoring treatment response in cancer patients after chemo- or radiotherapy is a very promising approach to optimize cancer treatment. However, the timing of the PET/CT-based evaluation of reduction in viable tumor tissue is a crucial question. We investigated how to plan and analyze studies to optimize this timing.
General considerations about studying the optimal timing are given and four fundamental steps are illustrated using data from a published study.
The optimal timing should be examined by optimizing the schedule with respect to predicting the overall individual time course we can observe in the case of dense measurements. The optimal timing needs not to and should not be studied by optimizing the association with the prognosis of the patient.
The optimal timing should be examined in specific ‘schedule optimizing studies’. These should be clearly distinguished from studies evaluating the prognostic value of a reduction in viable tumor tissue.
PMCID: PMC3477720  PMID: 23133795
cancer; response evaluation; prognostic value; optimal schedule
18.  Non-surgical treatment of hip osteoarthritis. Hip school, with or without the addition of manual therapy, in comparison to a minimal control intervention: Protocol for a three-armed randomized clinical trial 
Hip osteoarthritis is a common and chronic condition resulting in pain, functional disability and reduced quality of life. In the early stages of the disease, a combination of non-pharmacological and pharmacological treatment is recommended. There is evidence from several trials that exercise therapy is effective. In addition, single trials suggest that patient education in the form of a hip school is a promising intervention and that manual therapy is superior to exercise.
This is a randomized clinical trial. Patients with clinical and radiological hip osteoarthritis, 40-80 years of age, and without indication for hip surgery were randomized into 3 groups. The active intervention groups A and B received six weeks of hip school, taught by a physiotherapist, for a total of 5 sessions. In addition, group B received manual therapy consisting of joint manipulation and soft-tissue therapy twice a week for six weeks. Group C received a self-care information leaflet containing advice on "live as usual" and stretching exercises from the hip school. The primary time point for assessing relative effectiveness is at the end of the six weeks intervention period with follow-ups after three and 12 months.
Primary outcome measure is pain measured on an eleven-point numeric rating scale. Secondary outcome measures are the hip dysfunction and osteoarthritis outcome score, patient's global perceived effect, patient specific functional scale, general quality of life and hip range of motion.
To our knowledge this is the first randomized clinical trial comparing a patient education program with or without the addition of manual therapy to a minimal intervention for patients with hip osteoarthritis.
Trial registration
ClinicalTrials NCT01039337
PMCID: PMC3112433  PMID: 21542914
19.  PET/CT without capacity limitations: a Danish experience from a European perspective 
European Radiology  2011;21(6):1277-1285.
We report the 3-year clinical experience of a large new Danish PET/CT centre without capacity limitations in relation to national and European developments.
The use of PET/CT in cancer was registered from early 2006 to early 2009 to judge the impact on patient management and to compare it with national and European trends.
6056 PET/CT examinations were performed in 4327 patients. Activity increased by 86 examinations per month compared with the same month the year before. Referrals came primarily from oncology (23.0%), haematology (21.6%), surgery (12.6%), internal medicine (12.7%) and gynaecology (5.5%). Referral indications were diagnosis (31.3%), staging (22.3%), recurrence detection (21.2%), response evaluation (17.0%) and other (8.2%). Response from nearly 60% of users showed that PET/CT caused a change in diagnosis and/or staging and/or treatment plan in 36.0% of cases. During the study period, there was a steep increase in the national use of FDG and in the European use of PET/CT.
We recorded a constantly increasing use of PET/CT that caused a change in diagnosis and/or staging and/or treatment plan in 36.0% of cases. In line with national and European trends this may suggest a shift in favour of functional rather than anatomical imaging.
PMCID: PMC3088822  PMID: 21274717
Radionuclide imaging; PET/CT; Referral pattern; Indications; Clinical impact
20.  Parent’s Age and the Risk of Oral Clefts 
Epidemiology (Cambridge, Mass.)  2005;16(3):311-316.
Some malformations are clearly associated with older maternal age, but the effect of older age of the father is less certain. The aim of this study is to determine the degree to which maternal age and paternal age independently influence the risk of having a child with oral clefts.
Among the 1,489,014 live births in Denmark during 1973–1996, there were 1920 children with nonsyndromic cleft lip with or without cleft palate and 956 children with nonsyndromic cleft palate. We used logistic regression to assess the impact of parental age on the occurrence of cleft lip with or without cleft palate and cleft palate. Interaction between mother’s and father’s age was included in the analysis.
Separate analyses of mother’s and father’s age showed that older age was associated with increased risk of both cleft lip with or without cleft palate and cleft palate only. In a joint analysis, both maternal and paternal ages were associated with the risk of cleft lip with or without cleft palate, but the contribution of each was dependent on the age of the other parent. In the analysis of cleft palate only, the effect of maternal age disappeared, leaving only paternal age as a risk factor.
Both high maternal age and high paternal age were associated with cleft lip with or without cleft palate. Higher paternal age but not maternal age increased the risk of cleft palate only.
PMCID: PMC2839123  PMID: 15824545
21.  Time Trend of the Prevalence of Hepatitis E Antibodies among Farmers and Blood Donors: A Potential Zoonosis in Denmark 
Antibody to hepatitis E virus (anti-HEV) is prevalent in Western countries, where clinical hepatitis E is rarely reported. The aim of this study was to determine the prevalence of anti-HEV among Danish blood donors and Danish farmers. In addition, we compared the prevalence among 2 sets of serum samples obtained from blood donors 20 years apart.
Samples from 291 Danish farmers and 169 blood donors that were collected in 1983 and samples from 461 blood donors that were collected in 2003 were tested for anti-HEV. Relevant information on HEV exposure was collected by self-administered questionnaire.
Anti-HEV testing was performed on samples after 20 years of storage at −20°C. The prevalence of anti-HEV was 50.4% among farmers and 32.9% among donors in 1983 and 20.6% among donors in 2003 (P < .05). Presence of anti-HEV was significantly correlated with increasing age in all 3 groups (P < .05). Among donors who had serum samples obtained in 2003, age, contact with horses, and the presence of antibody to hepatitis A virus were associated with the presence of anti-HEV in multivariate analysis. Among farmers, only age was independently associated with the presence of anti-HEV.
Anti-HEV was highly prevalent among Danes but has decreased in prevalence over the past 50 years. Our study supports the hypothesis that HEV infection in Denmark may be an asymptomatic zoonotic infection.
PMCID: PMC2803052  PMID: 18781880
22.  High probability of disease in angina pectoris patients: Is clinical estimation reliable? 
According to most current guidelines, stable angina pectoris patients with a high probability of having coronary artery disease can be reliably identified clinically.
To examine the reliability of clinical evaluation with or without an at-rest electrocardiogram (ECG) in patients with a high probability of coronary artery disease.
A prospective series of 357 patients referred for coronary angiography (CA) for suspected stable angina pectoris were examined by a trained physician who judged their type of pain and Canadian Cardiovascular Society grade of pain. Pretest likelihood of disease was estimated, and all patients underwent myocardial perfusion scintigraphy (MPS) followed by CA an average of 78 days later. For analysis, the investigators focused on the approximate groups of patients with more severe disease, ie, typical angina (n=187), Canadian Cardiovascular Society grade 2 pain or higher (n=176) or high (higher than 85%) estimated pretest likelihood of disease (n=142).
In the three groups, 34% to 39% of male patients and 65% to 69% of female patients had normal MPS, while 37% to 38% and 60% to 71%, respectively, had insignificant findings on CA. Of the patients who had also an abnormal at-rest ECG, 14% to 21% of men and 42% to 57% of women had normal MPS. Sex-related differences were statistically significant.
Clinical prediction appears to be unreliable. Addition of at-rest ECG data results in some improvement, particularly in male patients, but it makes the high probability groups so small that the addition appears to be of limited clinical relevance.
PMCID: PMC2651943  PMID: 17593989
Angina; Angiography; Coronary artery disease; Diagnosis; Ischemia; Perfusion; Scintigraphy
23.  Diagnosis and treatment of musculoskeletal chest pain: design of a multi-purpose trial 
Acute chest pain is a major health problem all over the western world. Active approaches are directed towards diagnosis and treatment of potentially life threatening conditions, especially acute coronary syndrome/ischemic heart disease. However, according to the literature, chest pain may also be due to a variety of extra-cardiac disorders including dysfunction of muscles and joints of the chest wall or the cervical and thoracic part of the spine. The diagnostic approaches and treatment options for this group of patients are scarce and formal clinical studies addressing the effect of various treatments are lacking.
We present an ongoing trial on the potential usefulness of chiropractic diagnosis and treatment in patients dismissed from an acute chest pain clinic without a diagnosis of acute coronary syndrome. The aims are to determine the proportion of patients in whom chest pain may be of musculoskeletal rather than cardiac origin and to investigate the decision process of a chiropractor in diagnosing these patients; further, to examine whether chiropractic treatment can reduce pain and improve physical function when compared to advice directed towards promoting self-management, and, finally, to estimate the cost-effectiveness of these procedures. This study will include 300 patients discharged from a university hospital acute chest pain clinic without a diagnosis of acute coronary syndrome or any other obvious cardiac or non-cardiac disease. After completion of the clinic's standard cardiovascular diagnostic procedures, trial patients will be examined according to a standardized protocol including a) a self-report questionnaire; b) a semi-structured interview; c) a general health examination; and d) a specific manual examination of the muscles and joints of the neck, thoracic spine, and thorax in order to determine whether the pain is likely to be of musculoskeletal origin. To describe the patients status with regards to ischemic heart disease, and to compare and indirectly validate the musculoskeletal diagnosis, myocardial perfusion scintigraphy is performed in all patients 2–4 weeks following discharge. Descriptive statistics including parametric and non-parametric methods will be applied in order to compare patients with and without musculoskeletal chest pain in relation to their scintigraphic findings. The decision making process of the chiropractor will be elucidated and reconstructed using the CART method. Out of the 300 patients 120 intended patients with suspected musculoskeletal chest pain will be randomized into one of two groups: a) a course of chiropractic treatment (therapy group) of up to ten treatment sessions focusing on high velocity, low amplitude manipulation of the cervical and thoracic spine, mobilisation, and soft tissue techniques. b) Advice promoting self-management and individual instructions focusing on posture and muscle stretch (advice group). Outcome measures are pain, physical function, overall health, self-perceived treatment effect, and cost-effectiveness.
This study may potentially demonstrate that a chiropractor is able to identify a subset of patients suffering from chest pain predominantly of musculoskeletal origin among patients discharged from an acute chest pain clinic with no apparent cardiac condition. Furthermore knowledge about the benefits of manual treatment of patients with musculoskeletal chest pain will inform clinical decision and policy development in relation to clinical practice.
Trial registration
NCT00462241 and NCT00373828
PMCID: PMC2315652  PMID: 18377636
24.  Counting drugs to understand the disease: The case of measuring the diabetes epidemic 
Diabetes prevalence increases globally with severe consequences for afflicted individuals and societies. Data on diabetes incidence and diabetes related mortality on a population level are, however, scarce. As an alternative to dedicated studies it has been suggested to use pharmacoepidemiological databases that are readily available, at least in the Nordic countries.
For all 470,000 inhabitants in Funen County, Denmark, in the period 1992–2003, data on gender, date of birth, death and migration to and from the county, and any filled prescriptions of an anti-diabetic medication was obtained from the Odense Pharmaco-Epidemiological Database.
Prevalence odds for use of an anti-diabetic medication rose annually 3.5% (95% confidence interval: 3.1%, 3.9%) for females, 4.5% (4.0%, 4.9%) for males. Corresponding incidence rates annually rose 4.8% (3.8%, 5.8%) for females, 4.5% (3.5%, 5.4%) for males. Mortality rates among treated annually declined 2.8% (1.4%, 4.1%) among females, 2.2% (0.9%, 3.5%) among males. The disequilibrium in absolute numbers between incidence and mortality among treated was the main driver for the increasing prevalence, while concurrent trends in incidence and diabetes related mortality only marginally affected prevalence trends. Trend estimates were insensitive to varying the length of the run-in period used for determining treatment status, except when using the naive and methodologically flawed run-in period of variable length.
While pharmacoepidemiological databases provide a useful tool for monitoring pharmacologically treated diabetes, a dedicated diabetes database covering all prevalents and incidents is needed for a more detailed analysis of underlying causes and trends.
PMCID: PMC1805738  PMID: 17313683

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