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1.  Endoscopic treatment of post‐surgical bile duct injuries: long term outcome and predictors of success 
Gut  2007;56(11):1599-1605.
To analyse the short and long term outcome of endoscopic stent treatment after bile duct injury (BDI), and to determine the effect of multiple stent treatment.
Design, setting and patients
A retrospective cohort study was performed in a tertiary referral centre to analyse the outcome of endoscopic stenting in 67 patients with cystic duct leakage, 26 patients with common bile duct leakage and 110 patients with a bile duct stricture.
Main outcome measures
Long term outcome and independent predictors for successful stent treatment.
Overall success in patients with cystic duct leakage was 97%. In patients with common bile duct leakage, stent related complications occurred in 3.8% (n = 1). The overall success rate was 89% (n = 23). In patients with a bile duct stricture, stent related complications occurred in 33% (n = 36) and the overall success rate was 74% (n = 81). After a mean follow up of 4.5 years, liver function tests did not identify “occult” bile duct strictures. Independent predictors for outcome were the number of stents inserted during the first procedure (OR 3.2 per stent; 95% CI 1.3 to 8.4), injuries classified as Bismuth III (OR 0.12; 95% CI 0.02 to 0.91) and IV (OR 0.04; CI 0.003 to 0.52) and endoscopic stenting before referral (OR 0.24; CI 0.06 to 0.88). Introduction of sequential insertion of multiple stents did not improve outcome (before 77% vs after 66%, p = 0.25), but more patients reported stent related pain (before 11% vs after 28%, p = 0.02).
In patients with a postoperative bile duct leakage and/or strictures, endoscopic stent treatment should be regarded as the choice of primary treatment because of safety and favourable long term outcome. Apart from the early insertion of more than one stent, the benefit from sequential insertion of multiple stents did not become readily apparent from this series.
PMCID: PMC2095661  PMID: 17595232
2.  Update of the Preventive Antibiotics in Stroke Study (PASS): statistical analysis plan 
Trials  2014;15(1):382.
Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes.
The primary outcome is the score on the modified Rankin Scale (mRS), assessed by ordinal logistic regression analysis according to a proportional odds model. Secondary analysis of the primary outcome is the score on the mRS dichotomized as a favorable outcome (mRS 0 to 2) versus unfavorable outcome (mRS 3 to 6). Secondary outcome measures are death rate at discharge and 3 months, infection rate during hospital admission, length of hospital admission, volume of post-stroke care, use of antibiotics during hospital stay, quality-adjusted life years and costs. Complications of treatment, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported as safety outcomes.
The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection and will be analyzed according to this pre-specified SAP.
Trial registration
Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.
PMCID: PMC4195873  PMID: 25269598
stroke; infection; antibiotics; randomized clinical trial; statistical analysis plan
3.  Risk Factors for the Presence of Anal Intraepithelial Neoplasia in HIV+ Men Who Have Sex with Men 
PLoS ONE  2013;8(12):e84030.
Anal Intraepithelial Neoplasia (AIN) is present in the majority of HIV+ men who have sex with men (MSM) and routine AIN-screening is subject of discussion. In this study we analysed a wide range of potential risk factors for AIN in order to target screening programs.
We screened 311 HIV+ MSM by high resolution anoscopy, with biopsies of suspect lesions. HIV-parameters, previous sexual transmitted infections (STI’s), anal pathology, sexual practices and substance use were analysed in relation to AIN by uni- and multivariable logistic regression.
AIN (any grade) was found in 175/311 MSM (56%), high grade (HG)AIN in 30%. In the univariable analysis, years since HIV diagnosis, years of antiretroviral therapy (cART) and anal XTC use decreased AIN risk, while a history of anogenital warts and use of GHB (γ-hydroxybutyric acid) increased this risk. In the multivariable analysis three parameters remained significant: years of cART (OR=0.92 per year, p=0.003), anal XTC use (OR=0.10, p=0.002) and GHB use (OR=2.60, p=0.003). No parameters were significantly associated with HGAIN, but there was a trend towards increased risk with anal enema use prior to sex (>50 times ever; p=0.07) and with a history of AIN (p=0.06). CD4 count, STI’s, anal pathology, smoking, number of sex partners and anal fisting were not associated with (HG)AIN.
GHB use increases the risk for AIN, while duration of cART and anal XTC use are negatively correlated with AIN. Given the high prevalence of AIN in HIV+ MSM, these associations are not helpful to guide a screening program.
PMCID: PMC3867484  PMID: 24367625
4.  The PanAM study: a multi-center, double-blinded, randomized, non-inferiority study of paracetamol versus non-steroidal anti-inflammatory drugs in treating acute musculoskeletal trauma 
Acute musculoskeletal trauma, including strains, sprains or contusions, occur frequently. Pain management is a crucial component of treatment. However, there is no convincing evidence which drug is superior in managing pain in these patients. The aim of the PanAM Study is to compare analgesic efficacy of three strategies of pain management: paracetamol, diclofenac, or a combination of both in patients with acute musculoskeletal trauma.
The PanAM Study is a multi-center, double blind randomized controlled trial with non-inferiority design. Included are adult patients presenting to an academic, urban Emergency Department or to a General Practice with acute, blunt, traumatic limb injury. In total, 547 patients will be included using a predefined list of exclusion criteria, to be allocated by randomization to treatment with paracetamol + placebo diclofenac, diclofenac + placebo paracetamol or paracetamol + diclofenac. The hypothesis is that paracetamol will not be inferior to treatment with diclofenac, or the combination of both. Primary outcome will be between-group differences in decrease in pain, measured with Numerical Rating Scales at baseline and at 90 minutes after study drug administration. Secondary outcomes are Numerical Rating Scales at 30 and 60 minutes and measured frequently during three consecutive days after discharge; occurrence of adverse effects; patient satisfaction and an analysis of quality of life and cost-effectiveness. Recruitment started July 2013 and is expected to last a year.
With this multi-center randomized clinical trial we will investigate whether treatment with paracetamol alone is not inferior to diclofenac alone or a combination of both drugs in adult patients with acute musculoskeletal trauma. The main relevance of the trial is to demonstrate the benefits and risks of three commonly used treatment regimens for musculoskeletal trauma. Data that lead to the prevention of severe Non-Steroidal Anti-Inflammatory Drugs-related adverse effects might be gathered.
Trial registration
Dutch Trial Register ( NTR3982.
EudraCT database ( 201300038111.
PMCID: PMC4225513  PMID: 24256450
Wounds and injuries; Strains and sprains; Contusions; Analgesia; Pain; Paracetamol/acetaminophen; Anti-inflammatory agents; Non-steroidal; Costs and cost analysis
5.  Adverse Drug Events in Older Hospitalized Patients: Results and Reliability of a Comprehensive and Structured Identification Strategy 
PLoS ONE  2013;8(8):e71045.
Older patients are at high risk for experiencing Adverse Drug Events (ADEs) during hospitalization. To be able to reduce ADEs in these vulnerable patients, hospitals first need to measure the occurrence of ADEs, especially those that are preventable. However, data on preventable ADEs (pADEs) occurring during hospitalization in older patients are scarce, and no ‘gold standard’ for the identification of ADEs exists.
The study was conducted in three hospitals in the Netherlands in 2007. ADEs were retrospectively identified by a team of experts using a comprehensive and structured patient chart review (PCR) combined with a trigger-tool as an aid. This ADE identification strategy was applied to a cohort of 250 older hospitalized patients. To estimate the intra- and inter-rater reliabilities, Cohen’s kappa values were calculated.
Principal Findings
In total, 118 ADEs were detected which occurred in 62 patients. This ADE yield was 1.1 to 2.7 times higher in comparison to other ADE studies in older hospitalized patients. Of the 118 ADEs, 83 (70.3%) were pADEs; 51 pADEs (43.2% of all ADEs identified) caused serious patient harm. Patient harm caused by ADEs resulted in various events. The overall intra-rater agreement of the developed strategy was substantial (κ = 0.74); the overall inter-rater agreement was only fair (κ = 0.24).
The ADE identification strategy provided a detailed insight into the scope of ADEs occurring in older hospitalized patients, and showed that the majority of (serious) ADEs can be prevented. Several strategy related aspects, as well as setting/study specific aspects, may have contributed to the results gained. These aspects should be considered whenever ADE measurements need to be conducted. The results regarding pADEs can be used to design tailored interventions to effectively reduce harm caused by medication errors. Improvement of the inter-rater reliability of a PCR remains challenging.
PMCID: PMC3733642  PMID: 23940688
6.  Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain 
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear.
Renal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria.
Of 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; p < 0.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; p = 0.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, p = 0.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, p = 0.015;OR 0.52 (0.31-0.88), p = 0.014 respectively).
Long term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.
PMCID: PMC3626869  PMID: 23531228
7.  Recognition of adverse drug events in older hospitalized medical patients 
To assess medical teams’ ability to recognize adverse drug events (ADEs) in older inpatients.
The study cohort comprised 250 patients aged 65 years or older consecutively admitted to Internal Medicine wards of three hospitals in the Netherlands between April and November 2007. An independent expert team identified ADEs present upon admission or occurring during hospitalization by a structured retrospective patient chart review. For all ADEs identified, the expert team assessed causality, severity, preventability, and recognition by medical teams.
The medical teams did not recognize 19.9 % of all ADEs present upon admission {60.4 ADEs [95 % confidence interval (CI) 51.5–70.8] per 100 hospitalizations} and 20.3 % of all ADEs occurring during the hospital stay [47.2 ADEs (95 % CI 39.4–56.5) per 100 hospitalizations]. Unrecognized ADEs were significantly more often ADEs with possible causality (p=0.014, df=1), ADEs caused by medication errors (p<0.001, df=1), and ADEs not manifesting as new symptoms (p<0.001, df=1). The medical teams did not recognize 23.2 % of mild to moderately severe ADEs and 16.5 % of severe, life-threatening, or fatal ADEs. The recognition of ADEs varied with event type.
The recognition of ADEs by medical teams was substantial for those ADEs with evident causality and with clinically apparent and severe consequences. ADEs mimicking underlying pathologies with a lower severity went unrecognized much more often, as did those resulting only in abnormal laboratory values. Tools to improve the recognition of ADEs by medical teams should, therefore, focus on those ADEs that are more challenging to detect.
PMCID: PMC3536996  PMID: 22673927
Adverse drug events; Medication safety; Elderly; Hospital
8.  When to perform urodynamics before mid-urethral sling surgery for female stress urinary incontinence? 
Introduction and hypothesis
Development of a model that can predict in which group of women pre-operative urodynamics can be safely omitted.
Three hundred and eighty-one uncomplicated women who underwent pre-operative urodynamics were evaluated. A multivariate logistic regression model was developed based on medical history and physical examination predicting a high probability group of women with detrusor overactivity or a low (<20 cm H2O) mean urethral closure pressure and, therefore, are likely to benefit from urodynamics.
Women are likely to benefit from pre-operative urodynamics if they (1) are 53 years of age or older or (2) have a history of prior incontinence surgery and are at least 29 years of age or (3) have nocturia complaints and are at least 36 years of age.
If urogynaecologists omitted pre-operative urodynamics in women in the low probability group, in our population, pre-operative urodynamics would be reduced by 29%.
PMCID: PMC2815804  PMID: 19921082
Midurethral sling; Pre-operative; Stress urinary incontinence; Urodynamics
9.  Perspectives by patients and physicians on outcomes of mid-urethral sling surgery 
Introduction and hypothesis
The aim of this study is to determine patient expectations regarding wanted and unwanted sequels of mid-urethral sling (MUS) procedures and to identify mismatches during the physician–patient information exchange prior to MUS procedures.
A patient preference study (40 patients) and a questionnaire study with 20 experts as control group were conducted. Seventeen different sequels, defined by an expert team, were evaluated.
Both patients and expert physicians ranked cure and improvement of stress urinary incontinence as the most important goals of treatment. De novo urge urinary incontinence, requiring post-operative intermittent self-catheterisation and dyspareunia were considered to be the most important complications by patients. Time to resume work after the operation and dyspareunia were among the highest rated sequels in the patient group compared to re-operation and intra-operative complications in the expert group.
No differences were found in the five most important outcome parameters. In pre-operative counselling and future clinical trials, time to resume work and dyspareunia should be given more consideration by clinicians.
PMCID: PMC2832906  PMID: 19924367
Mid-urethral sling surgery; Outcome parameters; Patient expectations
10.  Temporary Closure of the Open Abdomen: A Systematic Review on Delayed Primary Fascial Closure in Patients with an Open Abdomen 
World Journal of Surgery  2008;33(2):199-207.
This study was designed to systematically review the literature to assess which temporary abdominal closure (TAC) technique is associated with the highest delayed primary fascial closure (FC) rate. In some cases of abdominal trauma or infection, edema or packing precludes fascial closure after laparotomy. This “open abdomen” must then be temporarily closed. However, the FC rate varies between techniques.
The Cochrane Register of Controlled Trials, MEDLINE, and EMBASE databases were searched until December 2007. References were checked for additional studies. Search criteria included (synonyms of) “open abdomen,” “fascial closure,” “vacuum,” “reapproximation,” and “ventral hernia.” Open abdomen was defined as “the inability to close the abdominal fascia after laparotomy.” Two reviewers independently extracted data from original articles by using a predefined checklist.
The search identified 154 abstracts of which 96 were considered relevant. No comparative studies were identified. After reading them, 51 articles, including 57 case series were included. The techniques described were vacuum-assisted closure (VAC; 8 series), vacuum pack (15 series), artificial burr (4 series), Mesh/sheet (16 series), zipper (7 series), silo (3 series), skin closure (2 series), dynamic retention sutures (DRS), and loose packing (1 series each). The highest FC rates were seen in the artificial burr (90%), DRS (85%), and VAC (60%). The lowest mortality rates were seen in the artificial burr (17%), VAC (18%), and DRS (23%).
These results suggest that the artificial burr and the VAC are associated with the highest FC rates and the lowest mortality rates.
PMCID: PMC3259401  PMID: 19089494
11.  Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials 
BMJ : British Medical Journal  2005;330(7503):1297.
Objective To determine the cost utility of medical co-prescription of heroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts.
Design Cost utility analysis of two pooled open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 430 heroin addicts.
Interventions Inhalable or injectable heroin prescribed over 12 months. Methadone (maximum 150 mg a day) plus heroin (maximum 1000 mg a day) compared with methadone alone (maximum 150 mg a day). Psychosocial treatment was offered throughout.
Main outcome measures One year costs estimated from a societal perspective. Quality adjusted life years (QALYs) based on responses to the EuroQol EQ-5D at baseline and during the treatment period.
Results Co-prescription of heroin was associated with 0.058 more QALYs per patient per year (95% confidence interval 0.016 to 0.099) and a mean saving of €12 793 (£8793, $16 122) (€1083 to €25 229) per patient per year. The higher programme costs (€16 222; lower 95% confidence limit €15 084) were compensated for by lower costs of law enforcement (- €4129; upper 95% confidence limit - €486) and damage to victims of crime (- €25 374; upper 95% confidence limit - €16 625). The results were robust for the use of national EQ-5D tariffs and for the exclusion of the initial implementation costs of heroin treatment. Completion of treatment is essential; having participated in any abstinence treatment in the past is not.
Conclusions Co-prescription of heroin is cost effective compared with treatment with methadone alone for chronic, treatment resistant heroin addicts.
PMCID: PMC558200  PMID: 15933353
12.  Imaging strategies for detection of urgent conditions in patients with acute abdominal pain: diagnostic accuracy study 
Objective To identify an optimal imaging strategy for the accurate detection of urgent conditions in patients with acute abdominal pain.
Design Fully paired multicentre diagnostic accuracy study with prospective data collection.
Setting Emergency departments of two university hospitals and four large teaching hospitals in the Netherlands.
Participants 1021 patients with non-traumatic abdominal pain of >2 hours’ and <5 days’ duration. Exclusion criteria were discharge from the emergency department with no imaging considered warranted by the treating physician, pregnancy, and haemorrhagic shock.
Intervention All patients had plain radiographs (upright chest and supine abdominal), ultrasonography, and computed tomography (CT) after clinical and laboratory examination. A panel of experienced physicians assigned a final diagnosis after six months and classified the condition as urgent or non-urgent.
Main outcome measures Sensitivity and specificity for urgent conditions, percentage of missed cases and false positives, and exposure to radiation for single imaging strategies, conditional imaging strategies (CT after initial ultrasonography), and strategies driven by body mass index and age or by location of pain.
Results 661 (65%) patients had a final diagnosis classified as urgent. The initial clinical diagnosis resulted in many false positive urgent diagnoses, which were significantly reduced after ultrasonography or CT. CT detected more urgent diagnoses than did ultrasonography: sensitivity was 89% (95% confidence interval 87% to 92%) for CT and 70% (67% to 74%) for ultrasonography (P<0.001). A conditional strategy with CT only after negative or inconclusive ultrasonography yielded the highest sensitivity, missing only 6% of urgent cases. With this strategy, only 49% (46% to 52%) of patients would have CT. Alternative strategies guided by body mass index, age, or location of the pain would all result in a loss of sensitivity.
Conclusion Although CT is the most sensitive imaging investigation for detecting urgent conditions in patients with abdominal pain, using ultrasonography first and CT only in those with negative or inconclusive ultrasonography results in the best sensitivity and lowers exposure to radiation.
PMCID: PMC3273785  PMID: 19561056

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