Preclinical and clinical studies have established the safety and immunogenicity of the chemically synthesised SPf66 malaria vaccine. The present study is a phase III randomised, double-blind, placebo-controlled, efficacy trial completed in La Tola, Colombia. 1548 volunteers over one year of age received three doses of either the vaccine (n = 738) or placebo (n = 810). Active and passive case detection methods were used to document clinical episodes of malaria among the study population. The follow-up period began one month after the third dose and lasted for one year. 168 and 297 episodes of Plasmodium falciparum malaria were documented in the SPf66 group and the placebo group, respectively; this corresponds to a crude protective efficacy of 38.8%. Incidence rates for first or only P falciparum malarial episodes were 22.3% per annum among the vaccinee group and 33.5% among the placebo group (RR = 1.5; 95% Cl 1.23, 1.84). Therefore, the protective efficacy of SPf66 against first or only episodes was 33.6% (95% Cl 18.8, 45.7), being highest in children aged 1-4 years (77%) and adults older than 45 years (67%). The estimated protective efficacy against second episodes was 50.5% (95% Cl 12.9-71.9). Our study shows that the chemically synthesised SPf66 malaria vaccine is safe, immunogenic, and protective against P falciparum malaria in semi-immune populations subject to natural challenge.

Artemisinin compounds clear parasitaemia more rapidly than other drugs do in both mild and severe malaria, but no advantage in clinical efficacy has been shown. We have compared artemether treatment with standard quinine treatment in Malawian children with cerebral malaria. 65 unconscious children were randomly allocated to intravenous quinine (n = 37) or intramuscular artemether (n = 28) treatment. The two groups were well matched for various prognostic features. Median parasite clearance times were shorter in the artemether group (28 [interquartile range 18-34] vs 40 [36-44] h in the quinine group, p = 0.0002). Coma resolution times were also shorter with artemether than with quinine (8 [4-15] vs 14 [10-36] h, p = 0.01).

Steroids have been beneficial in the treatment of demyelinating diseases with features similar to those of Guillain-Barré syndrome (GBS). However, steroid treatment of GBS has been disappointing; in an earlier trial oral prednisolone was ineffective, although the dose was low and the sample small. We assessed the benefit of a high-dose steroid regimen in a large sample of patients with GBS in a multicentre, randomised, double-blind trial. 242 adult patients were randomised to receive intravenous methylprednisolone (IVMP) 500 mg (124 patients) or a placebo (118) daily for 5 days. Patients were diagnosed by standard clinical criteria and entered the trial within 15 days of onset of neurological symptoms. All patients were too weak to run. Some patients received plasma exchange depending on the practice of their centre. Disability was graded on a scale from 0 (healthy) to 6 (dead) at intervals for 48 weeks. There was no significant difference in any outcome variable between patients treated with IVMP and those given placebo. The most important outcome was the difference between the groups in disability grade 4 weeks after randomisation, which was only a 0.06 grade (95% Cl -0.23 to 0.36) greater improvement in the IVMP than the placebo group. The 39 patients in the IVMP group who required ventilation did so for a median of 18 days, 9 days fewer than the 44 patients who had a placebo and required ventilation (95% Cl -9.6 to 27.6). Median time to walk unaided was 38 days in the IVMP patients and 50 days in the placebo patients (difference 12 days, (95% Cl -21.3 to 45.3). A short course of high-dose IVMP given early in GBS is ineffective.

The Randomised Intervention Treatment of Angina (RITA) trial is comparing the long-term effects of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery (CABG) in patients with one, two, or three diseased coronary arteries in whom equivalent revascularisation was deemed achievable by either procedure. This first report is for a mean 2.5 years' follow-up on the 1011 patients randomised. 59% had grade 3 or 4 angina, 59% had experienced angina at rest, and 55% had two or more diseased coronary arteries. The intended procedure was done in 98% of patients. In 97% of CABG patients all intended vessels were grafted. Dilatation of all treatment vessels was attempted in 87% of PTCA patients with an angiographic success rate per vessel of 87% (90% excluding occluded vessels). There have been 34 deaths (18 CABG, 16 PTCA) and the pre-defined combined primary event of death or definite myocardial infarction shows no evidence of a treatment difference (43 CABG, 50 PTCA; relative risk 0.88 [95% confidence interval 0.59-1.29]). 4% of PTCA patients required emergency CABG before discharge and a further 15% had CABG during follow-up. Within 2 years of randomisation 38% and 11% of the PTCA and CABG groups, respectively, required revascularisation procedure(s) or had a primary event (p < 0.001) and repeat coronary arteriography during follow-up was four times more common in PTCA than in CABG patients (31% vs 7%, p < 0.001). The prevalence of angina during follow-up was higher in the PTCA group (eg, 32% vs 11% at 6 months) but this difference became less marked after 2 years (31% vs 22%). Anti-anginal drugs were prescribed more frequently for PTCA patients. At 1 month CABG patients were less physically active, with greater coronary related unemployment and lower mean exercise times than the PTCA patients. Thereafter employment status, breathlessness, and physical activity improved, with no significant differences between the two treatment groups. At 1 year mean exercise times had increased by 3 min for both groups. These interim findings indicate that recovery after CABG, the more invasive procedure, takes longer than after PTCA. However, CABG leads to less risk of angina and fewer additional diagnostic and therapeutic interventions in the first 2 years than PTCA. So far, there is no significant difference in risk of death or myocardial infarction, and follow-up continues to at least five years.

Data from a non-randomised study have hinted that in patients with acute pulmonary embolism (PE), thrombolysis followed by heparin more rapidly reverses right-ventricular dysfunction and restores pulmonary tissue perfusion than does heparin alone. We have pursued this idea in a randomised protocol. 46 haemodynamically stable patients were randomised to recombinant tissue plasminogen activator (alteplase, rt-PA) 100 mg over 2 h followed by intravenous heparin and 55 to heparin alone. Right-ventricular wall motion was assessed qualitatively, and right-ventricular end diastolic area was estimated by planimetry from echocardiograms at baseline and at 3 and 24 hours. Pulmonary perfusion scans were obtained at baseline and 24 hours. In 39% of rt-PA patients but in only 17% of heparin alone patients right-ventricular wall motion at 24 hours had improved from baseline and in 2% and 17%, respectively, it worsened (p = 0.005). rt-PA patients also had a significant decrease in right-ventricular end-diastolic area during the 24 hours after randomisation and a significant absolute improvement in pulmonary perfusion (14.6% vs 1.5%). No clinical episodes of recurrent PE were noted among rt-PA patients, but there were 2 fatal and 3 non-fatal clinically suspected recurrent PEs within 14 days in patients randomised to heparin alone. rt-PA rapidly improves right-ventricular function and pulmonary perfusion among patients with PE and may lead to a lower rate of adverse clinical outcomes.

In many cases of whiplash injury symptoms persist and do not respond to treatment. There is uncontrolled evidence to suggest that intracutaneous injections of sterile water might help. Since that route may be unacceptable to patients the subcutaneous route is used in the randomised trial reported here. 40 patients with whiplash syndrome, mean age 46 years (24-73) were given subcutaneous injections of 0.3-0.5 ml sterile water or saline over tender and trigger points in the neck and shoulder. A maximum of three treatments were given during the first two months of the study and the patients were followed up for 8 months. The accidents had occurred 4-6 years previously. X-ray examinations revealed no traumatic spinal lesions. Neck mobility and pain levels were evaluated by a physiotherapist immediately before and after the first treatment and after 1, 3, and 8 months. After 3 months, the mean total mobility of the cervical spine had increased by 39 degrees in the sterile water group and 6 degrees in the saline group (p < 0.05). Minimum and maximum levels of pain in the weeks just before treatment were evaluated by a visual analogue scale from 0 to 10. After 3 months the minimum pain level had fallen from 2.2 to 1.4 in the sterile water group but was not reduced in the saline group (p < 0.02); the maximum had fallen from 8.1 to 3.8 in the sterile water group and from 8.3 to 7.5 in the saline group (p < 0.001). After 3 months, 19 of 20 patients in the sterile water group assessed their condition as generally improved but only 6 in the saline group felt that they had got better. After 8 months there were still significant differences for minimum pain score and for mobility but not for maximum pain or for self-assessment of improvement.

Venous reflux was assessed by duplex scanning and descending phlebography in 98 limbs of 52 patients. There was moderately good agreement for deep vein reflux elicited by a standardised Valsalva manoeuvre, classified by a modified Kistner grading (0 to IV). The same grade was found in 58 limbs, with a difference of one grade in 27 limbs, and more than one grade in 13. Descending phlebography underestimated reflux in the lower leg compared with duplex scanning. The presence of reflux found on duplex scan correlated with the half-volume refilling time on a foot-volume plethysmogram with a below-knee tourniquet. There was no correlation between descending phlebography and the half-refilling time. Ascending phlebography showed post-thrombotic changes in 23 limbs. The duplex scan confirmed severe reflux (grades III and IV) in 14 of these 23 limbs, and demonstrated isolated reflux below normal valves in 4 other limbs. Severe reflux was seen on the descending phlebogram in only 10 of the 23 limbs with post-thrombotic changes. Duplex scanning may be a better method for detecting reflux than descending phlebography and is more acceptable to the patient. Ascending phlebography remains essential to display anatomical abnormalities found in some postthrombotic limbs that are not associated with reflux.

Meta-analysis of data from several controlled trials has shown that low-dose aspirin reduces the risk of pregnancy-induced hypertension (PIH) and intrauterine growth retardation (IUGR) in women at high risk of these disorders. We have assessed the efficacy of low-dose aspirin in women judged to be at moderate risk. Women were included on prophylactic criteria--age under 18 or over 40 years, mild or moderate chronic hypertension (diastolic pressure between 90 and 110 mm Hg), nephropathy with normal renal function and blood pressure, history of PIH or IUGR, and twin pregnancy--or therapeutic criteria--PIH or early signs of IUGR in current pregnancy. Eligible women were randomly assigned treatment with 50 mg aspirin daily until delivery (583) or no treatment (523); 18 and 46 women, respectively, were lost to follow-up. The groups were well matched for baseline characteristics. We found no differences between the no-treatment and aspirin groups in numbers of spontaneous (5 vs 2) or therapeutic (1 vs 2) abortions, stillbirths (14 vs 13), perinatal mortality (35.7 vs 28.6 per 1000 births), mean birthweight (2858 [SD 729] vs 2874 [795] g), proportion of infants with birthweights below the 10th centile (95 [18.3%] vs 117 [19.0%]), or births before 37 weeks' gestation (184 [35.6%] vs 209 [33.9%]). Nor did the groups differ in the frequency of PIH with or without proteinuria (51 [15.2%] vs 81 [19.3%]). There was no difference in mean birthweight between the treatment groups in separate analyses according to criteria for trial entry and week of gestation at randomisation. Our study gives little support to the notion that low-dose aspirin is beneficial in women at moderate risk of PIH or IUGR.

Aminoglycosides are usually given in two or three divided doses. A once-daily regimen might be more effective and less toxic. We have conducted a randomised trial in consecutive patients with serious infections for whom an aminoglycoside seemed warranted. Exclusion criteria were neutropenia or severely impaired renal function. 123 patients were enrolled. For efficacy analysis only those patients were considered in whom treatment with the aminoglycoside was not stopped within 72 h (n = 67); toxicity was analysed on patients receiving aminoglycosides for more than 48 h and not using other nephrotoxic medication (n = 85). Gentamicin 4 mg/kg every day (OD) or gentamicin 1.33 mg/kg three times daily (MD) (with dose-reduction in case of renal dysfunction) were given intravenously. In almost all patients intravenous amoxycillin 1 g every 6 h was also started. Baseline characteristics were comparable in both arms. A good clinical response was observed in 32/35 (91%) of the OD and in 25/32 (78%) in the MD group (difference 13%, 95% confidence interval -6.4% to +26.9%). 2 patients in each group died with uncontrolled infection. An insufficient bacteriological response (persistent positive cultures, resistance, or superinfection) was observed in 2 patients with OD and 3 patients with MD. In patients treated for more than 48 h duration of therapy and mean doses were 7.0 days (1590 mg) and 7.4 days (1672 mg) in OD and MD respectively. Mean first serum trough/peak levels were 0.6/10.2 mg/L and 1.4/5.2 mg/L. Nephrotoxicity (a rise in serum creatinine of 45 mumol/L or more) developed in 2/40 (5%) in OD and 11/45 (24%) in MD (p = 0.016). Risk factors for nephrotoxicity were duration of therapy and baseline creatinine clearance rate. High-tone audiometry was performed when possible; no significant differences were found in hearing loss (3/12 and 3/11) or prodromal signs of ototoxicity (5/12 and 4/11). A once-daily dosing regimen of gentamicin is at least as effective as and is less nephrotoxic than more frequent dosing.

It is customary to tail off the dose of oral steroids after treatment of an acute exacerbation of asthma; the main reason for this practice is to avoid rebound asthma. We have carried out a randomised double-blind study to find out whether a tapering course of oral prednisolone has any advantage over an abruptly terminated course of prednisolone for an episode of acute asthma requiring hospital admission. We studied 35 patients admitted to hospital with acute asthma; their mean peak expiratory flow rate (PEFR) on admission was 173 L/min and their mean age was 32 years (range 18-55); all were using inhaled steroids on discharge (mean dose 908 micrograms daily). Each patient received 40 mg enteric-coated prednisolone daily for 10 days followed by a tapering course of either prednisolone 5 mg tablets (active taper) or identical placebo tablets (placebo taper), reducing from 7 tablets on day 11 to no tablets by day 18. The primary outcome measure was the PEFR on waking. Both groups responded well to treatment by day 10 (mean morning PEFR: active taper group 396 L/min, placebo taper group 391 L/min). There was no further significant change in PEFR in either group during the 7 days of active or placebo tapering or during the following 10 days (repeated measures analysis of variance, active vs placebo, p = 0.82). The groups were also similar in terms of secondary outcome measures--symptom scores, PEFR after morning bronchodilator treatment, evening PEFR, and treatment failures. This study suggests that steroid tapering is unnecessary in acute asthma; a personal asthma management plan with a reserve course of prednisolone may be more appropriate.