Translation of clinical prediction rules for febrile children to primary care practice: an observational cohort study

BackgroundClinical prediction rules (CPRs) to identify children with serious infections lack validation in low-prevalence populations, which hampers their implementation in primary care practice.AimTo evaluate the diagnostic value of published CPRs for febrile children in primary care.MethodAlarm signs of serious infection and clinical management were extracted from routine clinical practice data and manually recoded with a structured electronic data-entry program. Eight CPRs were selected from literature. CPR-variables were matched with alarm signs and CPRs were applied to the GPC-population. ‘Referral to emergency department (ED)’ was used as a proxy outcome measure for ‘serious infection’. CPR performance was assessed by calibration analyses, sensitivity, specificity, and area under the ROC-curve (ROC-area).ResultsA total of 9794 GPC-contacts were eligible, 54% male, median age 2.3 years (interquartile range 1.0–4.6 years) and 8.1% referred to ED. Frequencies of CPR-variables varied from 0.5% (cyanosis, drowsy) to 25% (temperature ≥40°C). Alarm signs frequently included in CPRs were ‘ill appearance’, ‘inconsolable’, and ‘abnormal circulatory or respiratory signs’. The height of the CPR’s predicted risks generally corresponded with being (or not being) referred to the ED in practice. However, calibration-slopes indicated that three CPRs underestimated the risk of serious infection in the GPC-population. Sensitivities ranged from 42% to 54%, specificities from 68% to 89%. ROC-areas ranged from 0.52 to 0.81, with best performance of CPRs for children aged <3 months.ConclusionPublished CPRs performed moderately well in the primary out-of-hours care population. Advice is given on how to improve translation of CPRs to primary care practice.     

Predicting prolonged duration of fever in children: a cohort study in primary care

Background

Fever in children in primary care is commonly caused by benign infections, but often worries parents. Information about the duration of fever and its predictors may help in reassuring parents, leading to diminished consultation of health care.

Aim

To determine which signs and symptoms predict a prolonged duration of fever in febrile children in primary care and evaluate whether C-reactive protein (CRP) measurement has an additive predictive value for these symptoms.

Design and setting

A prospective cohort study at a GPs’ cooperative (GPC) out-of-hours service.

Method

Children (aged 3 months to 6 years) presenting with fever as stated by the parents were included. Exclusion criteria were no communication in Dutch possible, previous enrolment in the study within 2 weeks, referral to the hospital directly after visiting the GPC, or no informed consent. The main outcome measure was prolonged duration of fever (>3 days) after initial contact.

Results

Four-hundred and eighty children were analysed, and the overall risk of prolonged duration was 13% (63/480). Multivariate analysis combined model of patient history and physical examination showed that ‘sore throat’ (OR 2.8; 95% CI = 1.30 to 6.01) and ‘lymph nodes palpable’ (OR 1.87; 95% CI = 1.01 to 3.49) are predictive for prolonged duration of fever. The discriminative value of the model was low (AUC 0.64). CRP had no additive value in the prediction of prolonged duration of fever (OR 1.00; 95% CI = 0.99 to 1.01).

Conclusion

The derived prediction model indicates that only a few signs and symptoms are related to prolonged duration of fever. CRP has no additional value in this model. Overall, because the discriminative value of the model was low, the duration of fever cannot be accurately predicted.     

The clinimetric properties of the World Health Organization Disability Assessment Schedule II in early inflammatory arthritis

OBJECTIVE: To assess the clinimetric properties of a new health-related quality of life (HRQOL) instrument, the World Health Organization Disability Assessment Schedule II (WHODAS II), in patients with early inflammatory arthritis. METHODS: Internal consistency as well as criterion, construct, and discriminative validity of the WHODAS II were assessed in 172 patients with early inflammatory arthritis who completed the WHODAS II, the Medical Outcomes Study Short Form 36 (SF-36), and other measures of disease severity, functioning, pain, depression, and resource use. Test-retest reliability of the WHODAS II was assessed by having a subset of 20 patients complete the WHODAS II a second time, 1 week after the first assessment. RESULTS: The WHODAS II had high internal consistency (Cronbach's alpha = 0.96 for patients working or in school and 0.93 for patients not working or in school). Test-retest intraclass correlation coefficients of the WHODAS II total score and subscales ranged from 0.82-0.96. The WHODAS II total score was strongly correlated with the SF-36 physical component score (Kendall's tau-b 0.51, P < 0.001) and moderately correlated with the SF-36 mental component score (tau-b 0.43, P < 0.001). WHODAS II correlations with disease outcomes ranged from Kendall's tau-b 0.15-0.55. The WHODAS II significantly differentiated between every aspect of disease severity assessed with the exception of measures of health resource use. CONCLUSION: The WHODAS II is a valid and reliable measure of HRQOL in cross-sectional studies of patients with early inflammatory arthritis. Research is still required to investigate potential item redundancy and determine its usefulness in longitudinal studies.     

Diagnostic approaches to suspected deep vein thrombosis and pulmonary embolism

The present paper aims at reviewing our present knowledge on the diagnosis of deep vein thrombosis and pulmonary embolism with a particular emphasis on clinically suspected outpatients. The various contemporary diagnostic tools (including clinical probability assessment, fibrin D-Dimer measurement, venous compression ultrasonography, ventilation/perfusion lung scintigraphy, helical CT scan, and echocardiography) are presented and rational sequential strategies are discussed in their various aspects, including validation in outcome studies, and cost-effectiveness analyses.     

Corneal epithelial stem cells for corneal injury

Introduction: Ocular surface diseases with limbal insufficiency represent a therapeutic challenge for restoring vision. This corneal deficiency includes both classical ocular diseases (as chemical burns) and rare ocular diseases (as congenital aniridia and ocular cicatricial pemphigoid).

Areas covered: Our understanding of limbal epithelial stem cells (LESCs) has increased the potential for treatment options. Pharmacological treatment strategies (as regenerating agent ophthalmic solutions) and especially surgical treatment strategies are available. Isolated LESCs can be produced by limbal primary cultures obtained from explants or cell suspensions. We review the latest cornea surgery techniques.

Expert opinion: The adjunction of human limbal mesenchymal cells as a support for limbal stem cell primary cultures appears to be of great interest. Recently, human-induced pluripotent stem cells have allowed the generation of minicorneal organoids. This potential means of creating a three-dimensional cornea with in vitro maturation opens up important research areas for corneal regeneration therapy.     

Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia

Hydrogen sulfide (H₂S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H₂S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit

Aims

The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.

Methods

Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.

Results

Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h^–1 at day 7; 17 ± 9.1 l h^–1 at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min^–1 at day 7 vs. 730 ± 344 ml min^–1 at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min^–1 for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.

Conclusions

The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.