Validating the prediction of lower urinary tract infection in primary care: sensitivity and specificity of urinary dipsticks and clinical scores in women.

BACKGROUND: Dipsticks are one of the most commonly used near-patient tests in primary care, but few clinical or dipstick algorithms have been rigorously developed. AIM: To confirm whether previously documented clinical and dipstick variables and algorithms predict laboratory diagnosis of urinary tract infection (UTI). DESIGN OF STUDY: Validation study. SETTING: Primary care. METHOD: A total of 434 adult females with suspected lower UTI had bacteriuria assessed using the European Urinalysis Guidelines. RESULTS: Sixty-six per cent of patients had confirmed UTI. The predictive values of nitrite, leucocyte esterase (+ or greater), and blood (haemolysed trace or greater) were confirmed (independent multivariate odds ratios = 5.6, 3.5, and 2.1 respectively). The previously developed dipstick rule--based on presence of nitrite, or both leucocytes and blood-- was moderately sensitive (75%) but less specific (66%; positive predictive value [PPV] 81%, negative predictive value [NPV] 57%). Predictive values were improved by varying the cut-off point: NPV was 76% for all three dipstick results being negative; the PPV was 92% for having nitrite and either blood or leucocyte esterase. Urine offensive smell was not found to be predictive in this sample; for a clinical score using the remaining three predictive clinical features (urine cloudiness, dysuria, and nocturia), NPV was 67% for none of the features, and PPV was 82% for three features. CONCLUSION: A clinical score is of limited value in increasing diagnostic precision. Dipstick results can modestly improve diagnostic precision but poorly rule out infection. Clinicians need strategies to take account of poor NPVs.

Effect of antibiotic prescribing strategies and an information leaflet on longer-term reconsultation for acute lower respiratory tract infection.

BACKGROUND: Limited evidence suggests that delayed prescribing may influence future consultation behaviour. AIM: To assess the effects of antibiotic prescribing strategy on reconsultation in the year following presentation with acute lower respiratory tract infection (LRTI). DESIGN OF STUDY: Balanced factorial randomised trial. SETTING: Primary care. METHOD: Eight hundred and seven subjects, aged>or=3 years, had acute illness presenting with cough as the main symptom, plus at least one symptom or sign from sputum, chest pain, dyspnoea or wheeze. The subjects were randomised to one of three prescribing strategies (antibiotics, delayed antibiotic, no antibiotic) and a leaflet. Prior antibiotic use and reconsultation were assessed by medical record review. RESULTS: Patients who had been prescribed antibiotic for cough in the previous 2 years were much more likely to reconsult (incidence rate ratio [IRR]=2.55, 95% confidence interval [CI]=1.62 to 4.01) and use of a delayed prescription strategy is associated with reduced reconsultation in this group. In those with prior antibiotic exposure, there was a 34% reduction in consultation rate in the no antibiotic group (IRR=0.66, 0.30 to 1.44, P=0.295) and a 78% reduction for the delayed antibiotic group (IRR=0.22, 0.10 to 0.49, P<0.001) when compared with those given immediate antibiotics. This effect was not observed in patients who had not been prescribed antibiotics in the previous 2 years; there was no reduction in consultations in the no antibiotic group (IRR=1.23, 0.79 to 1.92, P=0.358) or the delayed antibiotic group (1.19, 0.78 to 1.80, P=0.426). There was an increase in consultation rate with an information leaflet (IRR=1.27, 0.86 to 1.87, P=0.229). Past attendance with cough, or past attendance with other respiratory illness and smoking, also predicted reconsultation with cough. CONCLUSION: Delayed antibiotic prescribing for LRTI appears effective in modifying reconsultation behaviour, particularly in those with a prior history of antibiotic prescription for LRTI.

Predicting the duration of symptoms in lower respiratory tract infection.

BACKGROUND: Acute lower respiratory tract infection (LRTI) presenting in primary care has a long natural history. Antibiotic treatment makes little or no difference to the duration of cough. Limited information is currently available regarding predictors of illness duration. AIM: To determine predictors of illness duration in acute LRTI in primary care. DESIGN OF STUDY: Secondary analysis of trial data to identify independent predictors of illness severity and duration. SETTING: Primary care. METHOD: Eight-hundred and seven patients aged 3 years and over with acute illness (21 days or less) presenting with cough as the main symptom plus at least one symptom or sign from sputum, chest pain, dyspnoea, or wheeze were recruited to the study. Main outcomes were duration of symptoms (rated at least a slight problem) and more severe symptoms (rated at least moderately bad). RESULTS: The average duration of cough (rated at least a slight problem) was 11.7 days and was shorter among children (duration -1.72 days; 95% confidence interval [CI] = -3.02 to -0.41) or in individuals with a history of fever (-1.22 days; 95% CI = -0.18 to 2.27). The duration of cough was longer among those with restricted activities on the day they saw the doctor (+0.69 days for each point of a 7-point scale). The duration of more severe symptoms was longer in those with a longer duration of symptoms prior to consultation, with a more severe cough on the day of seeing the doctor, and restriction of activities on the day of seeing the doctor. CONCLUSION: Illness duration may be predicted from a limited number of clinical symptoms and from prior history. These findings should be subjected to validation in a separate population. To minimise expectation about rapid resolution of illness, adults who have restricted activities could be advised that they are likely to experience symptoms for longer.

Developing clinical rules to predict urinary tract infection in primary care settings: sensitivity and specificity of near patient tests (dipsticks) and clinical scores.

BACKGROUND: Suspected urinary tract infection (UTI) is one of the most common presentations in primary care. Systematic reviews have not documented any adequately powered studies in primary care that assess independent predictors of laboratory diagnosis. AIM: To estimate independent clinical and dipstick predictors of infection and to develop clinical decision rules. DESIGN OF STUDY: Validation study of clinical and dipstick findings compared with laboratory testing. SETTING: General practices in the south of England. METHOD: Laboratory diagnosis of 427 women with suspected UTI was assessed using European urinalysis guidelines. Independent clinical and dipstick predictors of diagnosis were estimated. RESULTS: UTI was confirmed in 62.5% of women with suspected UTI. Only nitrite, leucocyte esterase (+ or greater), and blood (haemolysed trace or greater) independently predicted diagnosis (adjusted odds ratios 6.36, 4.52, 2.23 respectively). A dipstick decision rule, based on having nitrite, or both leucocytes and blood, was moderately sensitive (77%) and specific (70%); positive predictive value (PPV) was 81% and negative predictive value (NPV) was 65%. Predictive values were improved by varying the cut-off point: NPV was 73% for all three dipstick results being negative, and PPV was 92% for having nitrite and either blood or leucocyte esterase. A clinical decision rule, based on having two of the following: urine cloudiness, offensive smell, and dysuria and/or nocturia of moderate severity, was less sensitive (65%) (specificity 69%; PPV 77%, NPV 54%). NPV was 71% for none of the four clinical features, and the PPV was 84% for three or more features. CONCLUSIONS: Simple decision rules could improve targeting of investigation and treatment. Strategies to use such rules need to take into account limited negative predictive value, which is lower than expected from previous research.

Longer term outcomes from a randomised trial of prescribing strategies in otitis media.

BACKGROUND: There are limited data about the longer-term outcomes in acute otitis media (AOM) when comparing the realistic alternatives of immediate prescription of antibiotics and a 'wait and see' or delayed prescribing policy. AIM: The aim was to assess the medium and longer term outcomes of two prescribing strategies for otitis media. DESIGN OF STUDY: Follow-up of a randomised controlled trial cohort. SETTING: Primary care. METHOD: Three-hundred and fifteen children aged 6 months to 10 years presenting with AOM were randomised to immediate antibiotics, or antibiotics delayed at the parents discretion 72 hours if the child still had significant otalgia or fever, or was not improving. Episodes of earache since study entry were documented, and a poor score (of 9 or more--the top 20%) on a reliable six-item functional rating scale (Cronbach's alpha = 0.75). RESULTS: The delayed prescribing strategy did not significantly increase reported episodes of earache in the 3 months since randomisation (odds ratio [OR] = 0.89; 95% confidence interval [CI] = 0.48 to 1.65) or over 1 year (OR = 1.03; 95% CI = 0.60 to 1.78) nor of poor scores on the function scale at 3 months (OR = 1.16; 95% CI = 0.61 to 2.22) or 1 year (OR = 1.12; 95% CI = 0.57 to 2.19), and controlling for subsequent antibiotic use after the randomised episode did not alter these estimates. The number of prior episodes of AOM documented in the doctor's notes predicted episodes of earache reported (0, 1, > or = 2 episodes, respectively; OR = 1, 2.42, 2.61; chi2 for trend 8.04; P<0.01). There was weaker evidence that prior episodes also predicted poor function at 1 year (OR = 1, 1.86, 2.28; chi2 for trend 5.49; P = 0.019). For children with recurrent AOM (two or more previous episodes documented in the doctor's notes, n = 43) there was possible evidence of fewer episodes of earache in the 3 months since study entry in the immediate antibiotic group (10% compared to 39% in the delayed group, chi2 4.8, P = 0.029), but no effect from randomisation to 1 year. CONCLUSIONS: For most children, delayed prescribing is not likely to have adverse longer-term consequences. Children with recurrent AOM are more likely to have poorer outcomes. Secondary analysis should be treated with caution and requires confirmation, but suggests that treating such children with antibiotics immediately may not alter longer-term outcomes.

Pregabalin: as adjunctive treatment of partial seizures.

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methylhexanoic acid, possesses anticonvulsant activity. Pregabalin binds with high affinity and specificity to voltage-gated calcium channel alpha(2)-delta proteins. The putative mechanism of action of the drug is reduced excitatory neurotransmitter release caused by binding to the alpha(2)-delta protein, resulting in allosteric modulation of P/Q-type voltage-gated calcium channels. In three well designed trials, oral pregabalin as adjunctive therapy in patients with refractory partial seizures was significantly (p < or = 0.0007) more effective than placebo in reducing seizure frequency when administered at dosages of 150-600 mg/day (as two or three divided doses). Adjunctive pregabalin produced an overall mean 41.3% improvement from baseline in 28-day seizure-free rate in four long-term (maximum exposure 1764 days), open-label studies in 1480 patients. CNS-related effects (e.g. dizziness and somnolence) were the most frequent dose-related treatment-emergent adverse events associated with adjunctive pregabalin therapy.

AlphaScreen kinase HTS platforms.

Kinases represents one of the most important family of targets in high throughput drug screening. Tyrosine kinases and serine/threonine kinases are known to play key roles in signal transduction as well as in cell growth and differentiation. Intense screening campaigns are underway in all major pharmaceuticals and large biotech companies to find kinase inhibitors for the treatment of inflammatory diseases, immunological disorders and cancer. The present contribution describes models that were developed to produce kinase assays amenable to HTS using AlphaScreen. Because of the flexibility allowed by AlphaScreen, kinase assays can be developed using direct or indirect approaches. Tyrosine kinase assays are usually performed with a direct format involving generic anti-phosphotyrosine antibodies while serine/threonine kinase assays are performed with an indirect format where specific antibodies are captured using protein A conjugated Acceptor beads. Streptavidin-coated Donor beads are used to capture either generic (ex. poly GT) or specific biotinylated substrates. Herein, are presented different methods to perform screening for inhibitors acting on the soluble beta-insulin receptor tyrosine kinase (IRKD), and on p38, a member of the MAP kinase family.

Importance of patient pressure and perceived pressure and perceived medical need for investigations, referral, and prescribing in primary care: nested observational study.

OBJECTIVE: To assess how pressures from patients on doctors in the consultation contribute to referral and investigation. DESIGN: Observational study nested within a randomised controlled trial. SETTING: Five general practices in three settings in the United Kingdom. PARTICIPANTS: 847 consecutive patients, aged 16-80 years. MAIN OUTCOMES MEASURES: Patient preferences and doctors' perception of patient pressure and medical need. RESULTS: Perceived medical need was the strongest independent predictor of all behaviours and confounded all other predictors. The doctors thought, however, there was no or only a slight indication for medical need among a significant minority of those who were examined (89/580, 15%), received a prescription (74/394, 19%), or were referred (27/125, 22%) and almost half of those investigated (99/216, 46%). After controlling for patient preference, medical need, and clustering by doctor, doctors' perceptions of patient pressure were strongly associated with prescribing (adjusted odds ratio 2.87, 95% confidence interval 1.16 to 7.08) and even more strongly associated with examination (4.38, 1.24 to 15.5), referral (10.72, 2.08 to 55.3), and investigation (3.18, 1.31 to 7.70). In all cases, doctors' perception of patient pressure was a stronger predictor than patients' preferences. Controlling for randomisation group, mean consultation time, or patient variables did not alter estimates or inferences. CONCLUSIONS: Doctors' behaviour in the consultation is most strongly associated with perceived medical need of the patient, which strongly confounds other predictors. However, a significant minority of examining, prescribing, and referral, and almost half of investigations, are still thought by the doctor to be slightly needed or not needed at all, and perceived patient pressure is a strong independent predictor of all doctor behaviours. To limit unnecessary resource use and iatrogenesis, when management decisions are not thought to be medically needed, doctors need to directly ask patients about their expectations.

Randomised controlled trial of effect of leaflets to empower patients in consultations in primary care.

OBJECTIVE: To assess the impact of leaflets encouraging patients to raise concerns and to discuss symptoms or other health related issues in the consultation. DESIGN: Randomised controlled trial. SETTING: Five general practices in three settings in the United Kingdom. PARTICIPANTS: 636 consecutive patients, aged 16-80 years, randomised to receive a general leaflet, a depression leaflet, both, or neither. MAIN OUTCOMES: Mean item score on the medical interview satisfaction scale, consultation time, prescribing, referral, and investigation. RESULTS: The general leaflet increased patient satisfaction and was more effective with shorter consultations (leaflet 0.64, 95% confidence interval 0.19 to 1.08; time 0.31, 0.0 to 0.06; interaction between both -0.045, -0.08 to-0.009), with similar results for subscales related to the different aspects of communication. Thus for a 10 minute consultation the leaflet increased satisfaction by 7% (seven centile points) and for a five minute consultation by 14%. The leaflet overall caused a small non-significant increase in consultation time (0.36 minutes, -0.54 to 1.26). Although there was no change in prescribing or referral, a general leaflet increased the numbers of investigations (odds ratio 1.43, 1.00 to 2.05), which persisted when controlling for the major potential confounders of perceived medical need and patient preference (1.87, 1.10 to 3.19). Most of excess investigations were not thought strongly needed by the doctor or the patient. The depression leaflet had no significant effect on any outcome. CONCLUSIONS: Encouraging patients to raise issues and to discuss symptoms and other health related issues in the consultation improves their satisfaction and perceptions of communication, particularly in short consultations. Doctors do, however, need to elicit expectations to prevent needless investigations.

Predictors of poor outcome and benefits from antibiotics in children with acute otitis media: pragmatic randomised trial.

OBJECTIVES: To identify which children with acute otitis media are at risk of poor outcome and to assess benefit from antibiotics in these children. DESIGN: Secondary analysis of randomised controlled trial cohort. SETTING: Primary care. PARTICIPANTS: 315 children aged 6 months to 10 years. INTERVENTION: Immediate or delayed (taken after 72 hours if necessary) antibiotics. MAIN OUTCOME MEASURE: Predictors of short term outcome: an episode of distress or night disturbance three days after child saw doctor. RESULTS: Distress by day three was more likely in children with high temperature (adjusted odds ratio 4.5, 95% confidence interval 2.3 to 9.0), vomiting (2.6,1.3 to 5.0), and cough (2.0, 1.1 to 3.8) on day one. Night disturbance by day three was more likely with high temperature 2.4 (1.2 to 4.8), vomiting (2.1,1.1 to 4.0), cough (2.3,1.3 to 4.2), and ear discharge (2.1, 1.2 to 3.9). Among the children with high temperature or vomiting, distress by day three was less likely with immediate antibiotics (32% for immediate v 53% for delayed, chi2=4.0; P=0.045, number needed to treat 5) as was night disturbance (26% v 59%, chi2=9.3; P=0.002; number needed to treat 3). In children without higher temperature or vomiting, immediate antibiotics made little difference to distress by day three (15% v 19%, chi2=0.74; P=0.39) or night disturbance (20% v 27%, chi2=1.6; P=0.20). Addition of cough did not significantly improve prediction of benefit. CONCLUSION: In children with otitis media but without fever and vomiting antibiotic treatment has little benefit and a poor outcome is unlikely.