Development and validation of a clinical prediction rule for acute appendicitis in children in primary care.

BACKGROUND: Recognising acute appendicitis in children presenting with acute abdominal pain in primary care is challenging. General practitioners (GPs) may benefit from a clinical prediction rule. OBJECTIVES: To develop and validate a clinical prediction rule for acute appendicitis in children presenting with acute abdominal pain in primary care. METHODS: In a historical cohort study data was retrieved from GP electronic health records included in the Integrated Primary Care Information database. We assigned children aged 4-18 years presenting with acute abdominal pain (≤ 7 days) to development (2010-2012) and validation (2013-2016) cohorts, using acute appendicitis within six weeks as the outcome. Multiple logistic regression was used to develop a prediction model based on predictors with > 50% data availability derived from existing rules for secondary care. We performed internal and external temporal validation and derived a point score to stratify risk of appendicitis into three groups, i.e. low-risk, medium-risk and high-risk. RESULTS: The development and validation cohorts included 2,041 and 3,650 children, of whom 95 (4.6%) and 195 (5.3%) had acute appendicitis. The model included male sex, pain duration (<24, 24-48, > 48 h), nausea/vomiting, elevated temperature (≥ 37.3 °C), abnormal bowel sounds, right lower quadrant tenderness, and peritoneal irritation. Internal and temporal validation showed good discrimination (C-statistics: 0.93 and 0.90, respectively) and excellent calibration. In the three groups, the risks of acute appendicitis were 0.5%, 7.5%, and 41%. CONCLUSION: Combined with further testing in the medium-risk group, the prediction rule could improve clinical decision making and outcomes.

Strengths and weaknesses of a stepped wedge cluster randomized design: its application in a colorectal cancer follow-up study.

OBJECTIVES: To determine the advantages and disadvantages of a stepped wedge design for a specific clinical application. STUDY DESIGN AND SETTING: The clinical application was a pragmatic cluster randomized surgical trial intending to find an increased percentage of curable recurrences in patients in follow-up after colorectal cancer. Advantages and disadvantages of the stepped wedge design were evaluated, and for this application, new advantages and disadvantages were presented. RESULTS: A main advantage of the stepped wedge design was that the intervention rolls out to all participants, motivating patients and doctors, and a large number of patients who were included in this study. The stepped wedge design increased the complexity of the data analysis, and there were concerns regarding the informed consent procedure. The repeated measurements may bring burden to patients in terms of quality of life, satisfaction, and costs. CONCLUSION: The stepped wedge design is a strong alternative for pragmatic cluster randomized trials. The known advantages hold, whereas most of the disadvantages were not applicable to this application. The main advantage was that we were able to include a large number of patients. Main disadvantages were that the informed consent procedure can be problematic and that the analysis of the data can be complex.

Exercise therapy for stress-related mental disorder, a randomised controlled trial in primary care.

BACKGROUND: to investigate whether a structured physical exercise programme (PEP) improves the recovery of general health in patients suffering from Stress-related Mental Disorder (SMD). STUDY DESIGN: randomised open trial in general practice. Patients from two regions in the Netherlands were included between September 2003 and December 2005, and followed up for 12 weeks. INTERVENTION: the patients were referred to a physical therapist for instruction in and monitoring of physical exercise of an intermediate intensity. Following the Dutch Guidelines for Healthy Physical Exercise, the patients were instructed to exercise at least five times a week, for at least 30 minutes per day. CONTROL GROUP: usual care from the GP OUTCOME: Primary: improvement of general health after 6 weeks according to the 'general health' dimension of the Short-Form 36.Secondary: total days off work, percentage that resumed work after 6 and 12 weeks, change in distress score and change in remaining SF36 dimensions after 6 and 12 weeks. RESULTS: out of 102 randomised patients (mean age 43, 60 (59%) female), 70 (68%) completed the trial, of whom 31 were in the intervention group. After 6 weeks, the mean (SD) general health score was 54.6 (22.1) for the intervention group and 57.5 (19.2) for the controls. The corresponding effect size (Cohen's d with 95% confidence interval) from analysis of covariance was -0.06 (-0.41, 0.30) indicating no effect on general health. No significant effects of the intervention were detected for any secondary outcome parameter either. CONCLUSION: Notwithstanding the relatively high drop-out rate, our results suggest that referral to a physical therapist for structured physical exercise is not likely to be very effective in improving recovery from SMD. TRIAL REGISTRY: Current Controlled Trials ISRCTN15609105.

Pharmacogenetics of glucose-lowering drug treatment: a systematic review.

Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication. A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs. Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides. Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers. Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.

Effectiveness of neuronavigation in resecting solitary intracerebral contrast-enhancing tumors: a randomized controlled trial.

OBJECT: The goal of this study was to assess the impact of neuronavigation on the cytoreductive treatment of solitary contrast-enhancing intracerebral tumors and outcomes of this treatment in cases in which neuronavigation was preoperatively judged to be redundant. METHODS: The authors conducted a prospective randomized study in which 45 patients, each harboring a solitary contrast-enhancing intracerebral tumor, were randomized for surgery with or without neuronavigation. Peri- and postoperative parameters under investigation included the following: duration of the procedure; surgeon's estimate of the usefulness of neuronavigation; quantification of the extent of resection, determined using magnetic resonance imaging; and the postoperative course, as evaluated by neurological examinations, the patient's quality-of-life self-assessment, application of the Barthel index and the Karnofsky Performance Scale score, and the patient's time of death. The mean amount of residual tumor tissue was 28.9% for standard surgery (SS) and 13.8% for surgery involving neuronavigation (SN). The corresponding mean amounts of residual contrast-enhancing tumor tissue were 29.2 and 24.4%, respectively. These differences were not significant. Gross-total removal (GTR) was achieved in five patients who underwent SS and in three who underwent SN. Median survival was significantly shorter in the SN group (5.6 months compared with 9 months, unadjusted hazard ratio = 1.6); however, this difference may be attributable to the coincidental early death of three patients in the SN group. No discernible important effect on the patients' 3-month postoperative course was identified. CONCLUSIONS: There is no rationale for the routine use of neuronavigation to improve the extent of tumor resection and prognosis in patients harboring a solitary enhancing intracerebral lesion when neuronavigation is not already deemed advantageous because of the size or location of the lesion.

MR urography for the preoperative evaluation of living renal donors.

The purpose of this study was to assess the image quality and diagnostic value of MR urography in detecting abnormalities of the urinary collecting system relevant for the preoperative evaluation of living renal donors. Study subjects were selected from the existing intravenous urography (IVU) reports: 18 consecutive patients with a duplication or another abnormality of the collecting system and 20 consecutive patients with normal anatomy. They underwent a respiratory-triggered 3D T2-weighted fast spin-echo acquisition after oral administration of furosemide, without and with abdominal compression. The MR images were evaluated by two independent blinded observers. The IVU was used as the standard of reference. Image quality of the MR urograms with compression was overall better than those without compression, and the former were regarded as adequate for the evaluation of small filling defects and deformities of the pelvis and calyces in 76-81% of the kidneys and 74-79% of the patients. Both observers correctly diagnosed all 13 kidneys with a partial or complete duplication. The image quality of MR urography was inadequate to evaluate the calyces and pelvis for small filling defects or deformities in approximately 25% of the patients; however, the technique was accurate in the detection of abnormalities of the urinary collecting system relevant for the preoperative evaluation of living renal donors.

Human tissue transglutaminase enzyme linked immunosorbent assay outperforms both the guinea pig based tissue transglutaminase assay and anti-endomysium antibodies when screening for coeliac disease.

UNLABELLED: Anti-endomysium antibodies (EMA) and antigliadin antibodies (AGA) are widely used when screening for coeliac disease (CD), although their specificity and sensitivity are suboptimal. The guinea pig tissue transglutaminase (tTG) assay also did not prove to be superior. A newly developed enzyme linked immunosorbent assay (Celikey), based on human tTG, might however have a better performance. We therefore investigated the sensitivity and specificity of this human IgA tTG assay in 101 patients with aspecific gastrointestinal complaints and compared this to guinea pig IgA tTG, AGA and EMA. A total of 52 patients with CD were investigated and 49 patients without CD. All had a small bowel biopsy. Our results showed that human IgA tTG had a sensitivity of 96% and a specificity of 100%. Guinea pig IgA-tTG had a sensitivity of 96% and a specificity of 92%. EMA had a sensitivity of 92% and a specificity of 90%. Both IgA AGA and IgG AGA had a sensitivity of 83% whilst having a specificity of 86% and 80% respectively. CONCLUSION: both the human IgA tissue transglutaminase enzyme linked immunosorbent assay and the guinea pig IgA tissue transglutaminase assay could better identify patients with coeliac disease than IgA anti-endomysium antibodies. Although in a larger series of control patients the specificity for the human IgA tissue transglutaminase enzyme linked immunosorbent assay might fall below 100%, in our opinion this is currently the serological method of choice in identifying patients with coeliac disease in the absence of IgA deficiency.