The safety and efficacy of ivermectin in the prevention of blindness from onchocerciasis have been established in many studies that have addressed the drug's effects on the front of the eye. We undertook a study with sufficient statistical power to detect an effect on optic nerve disease (OND), probably the main cause of blindness in the disorder. The trial was based in 34 mesoendemic communities in Kaduna State, Nigeria. Villagers aged 5 years and older were randomly assigned annual dosing with ivermectin or placebo for 3 years. Participants underwent medical and ophthalmological examinations before the first, third, and fourth treatments. 3522 villagers aged 15 and older were re-examined at least once. Skin-snip samples were taken at baseline for calculation of microfilarial load. The outcome measure was development of disc pallor accompanied by objective evidence of deterioration in visual function; 116 subjects (45 ivermectin-treated, 71 placebo-treated) showed such changes during the trial. The incidence rate ratio (ivermectin vs placebo) was 0.90 (95% CI 0.54-1.51) for subjects with loads of 0-10 mf (microfilariae) per mg skin and 0.52 (0.29-0.93) for subjects with more than 10 mf/mg. The incidence rate ratio varied little when account was taken of age, sex, presence of pre-existing disc pallor in one eye, previous use of diethylcarbamazine citrate, or doses of ivermectin or placebo received. There was evidence that ivermectin reduced the incidence of OND in subjects with microfilarial loads above 10 mf/mg but had little effect in those with lower loads. Sustained annual delivery of ivermectin could prevent a substantial proportion of onchocercal blindness in mesoendemic communities.

Although vitamin A deficiency in children seems to increase susceptibility to infection and community trials have shown that vitamin A supplementation can reduce childhood mortality from infectious diseases, the underlying biological mechanisms are largely unknown. We conducted a randomised, double-masked, placebo-controlled clinical trial among children in West Java, Indonesia, to determine whether vitamin A deficiency is associated with abnormalities in T-cell subsets and whether vitamin A supplementation affects T-cell subsets. We studied 55 children aged 3-6 years--30 with xerophthalmia and 25 without. Acutely malnourished children (< 80% of reference weight-for-height) were excluded. CD4/CD8 ratios and the proportions of circulating CD4 naive, CD4 memory, CD8, CD45RA, and CD8, CD45RO T-cell subsets were measured. Children with xerophthalmia had lower CD4/CD8 ratios (p < 0.08), lower proportions of CD4 naive T cells (p < 0.03), and higher proportions of CD8, CD45RO T cells (p < 0.04) than those without xerophthalmia. 26 children were given vitamin A supplementation (60 mg retinol equivalent) and 29 received placebo. 5 weeks later the vitamin A group had higher CD4/CD8 ratios (p < 0.001), higher proportions of CD4 naive T cells (p < 0.01), and lower proportions of CD8, CD45RO T cells (p < 0.05) than the placebo group. Vitamin-A-deficient children have underlying immune abnormalities in T-cell subsets and these abnormalities are reversible with vitamin A supplementation.

Most hip fractures seem to be related to trauma near the hip, so a controlled trial was conducted to investigate the effect of external hip protectors on the prevention of such fractures in residents of a nursing home. 10 of the 28 wards in the nursing home were randomised to receive external hip protectors; thus 167 women and 80 men were given protectors and 277 and 141 men no protectors. A fall register was set up for 2 treatment wards (45 residents) and 2 control wards (76 residents). There were 8 hip and 15 non-hip fractures in the hip-protector group and 31 hip and 27 non-hip fractures in the control group. The relative risk of hip fractures among women and men in the intervention group was 0.44 (95% CI 0.21-0.94). None of the 8 residents in the intervention group who had a hip fracture was wearing the device at the time of the fracture. 154 falls were registered and 20% of these falls produced a direct impact to the hip. In 25 falls direct impact to the hip was sustained at a time when hip protectors were not being worn, and 6 fractures were produced. The study indicates that external hip protectors can prevent hip fractures in nursing-home residents.

Transurethral microwave thermotherapy (TUMT) is a single-session, minimally invasive outpatient treatment for patients with symptoms of benign prostatic bladder outflow obstruction. We designed a prospective randomised trial to identify any placebo response. Patients with a Madsen symptom score over 8 for at least 6 months were eligible for study. Two measurements of urinary flow less than 15 mL/s and a residual urine of under 350 mL were also required for entry. Patients with renal dysfunction, upper urinary tract disease, co-existing bladder disease, and malignant prostatic change were excluded. 43 patients were studied: 21 were randomised to receive a sham treatment and 22 to thermotherapy. Sham treatments were done with the urethral applicator in situ. 40 patients were available for evaluation at 3 months. 2 patients had delayed follow-up and 1 patient randomised to TUMT has undergone transurethral resection. The thermotherapy group showed a 70% decrease (from 14.5 to 4.3) in the mean Madsen score, a 53% increase in flow-rate (8.5 to 13.0 mL/s), and 92% decrease in residual urine volume (147 to 12 mL). No significant change was seen in these mean indices in the sham group. There was no difference in the main complication of transient haematuria between the two groups. However, there was a 22% frequency of acute retention in the TUMT group. The results show little significant placebo component to the subjective and objective improvement that occurs in patients who have received TUMT.

Iron-deficient anaemic infants perform worse in tests of mental and motor development than do iron-sufficient infants of a comparable age. A randomised, double-blind trial was done to monitor the effects of iron supplementation on performance in the Bayley scales of mental and motor development among 12-18-month-old infants in Indonesia. Iron-deficient anaemic infants (n = 50) were assigned randomly to receive dietary ferrous sulphate or placebo for 4 month. Similar treatment randomisation was done among nonanaemic iron-deficient (n = 29) and iron-sufficient (n = 47) infants. Before intervention, the mean mental and motor scores of the iron-deficient anaemic infants were significantly (p < 0.01) lower than those of the nonanaemic iron-deficient and iron-sufficient classes. After intervention, developmental delays were reversed among iron-deficient anaemic infants who had received iron but they remained the same among placebo-treated iron-deficient anaemic infants. Neither ferrous sulphate nor placebo had significant effects on the scores of the other two iron-status classes. The poor performance of 12-18-month-old iron-deficient anaemic infants in the Bayley scales of mental and motor development can be improved to the level of performance of iron-sufficient infants by treatment with ferrous sulphate.

It is not clear whether high doses of inhaled steroids have a greater sparing effect than low doses on the requirement for systemic steroids. In a randomised, double-blind, multicentre study, we compared the effects of high-dose (1500 micrograms/day) and low-dose (300 micrograms/day) inhaled beclomethasone dipropionate (BDP) in patients with severe asthma requiring a daily oral prednisolone dose of 10-40 mg. During a 3-month run-in period, we tried to achieve optimum asthma control by means of oral steroid and inhaled BDP 300 micrograms/day. The patients were then allocated to high-dose (n = 71) or low-dose (n = 72) treatment by an independent observer who took into account various prognostic factors. BDP was administered by means of an aerosol inhaler with a spacer device. The dose of systemic steroid was reduced as much as possible during the 6-month study period while keeping the peak expiratory flow (PEF) constant and asthma clinically stable. There was no difference between the low-dose and high-dose treatment groups in the mean reduction in oral prednisolone dose achieved by the end of the study (5.2[ SD 7.9] vs 5.0 [9.4] mg/day). The maximum response to inhaled steroid was seen, however, only after several months' therapy in both groups. There were no differences between the groups in use of on-demand beta-agonist inhalations or in asthma symptoms, and PEF values were constant throughout the study. Both doses of BDP were well tolerated. High doses of inhaled steroid offer no further benefit over low doses in the maintenance treatment of severe steroid-dependent asthma when the inhaled steroid is administered with a spacer device.

Self-expanding metal stents are claimed to prolong biliary-stent patency, although no formal comparative trial between plastic and expandable stents has been done. In a prospective randomised trial, we assigned 105 patients with irresectable distal bile-duct malignancy to receive either a metal stent (49) or a straight polyethylene stent (56). Median patency of the first stent was significantly prolonged in patients with a metal stent compared with those with a polyethylene stent (273 vs 126 days; p = 0.006). The major cause of stent dysfunction was tumour ingrowth in the metal-stent group and sludge deposition in the polyethylene-stent group. Treatment after any occlusion included placement of a polyethylene stent. In the metal-stent group none of 14 second stents occluded, whereas 11 of 23 (48%) second stents clogged in the polyethylene-stent group (p = 0.002). Overall median survival was 149 days and did not differ significantly between treatment groups. Incremental cost-effectiveness analysis showed that initial placement of a metal stent results in a 28% decrease of endoscopic procedures. Self-expanding metal stents have a longer patency than polyethylene stents and offer adequate palliation in patients with irresectable malignant distal bile-duct obstruction.

The hypothesis that patients with chronic obstructive pulmonary disease (COPD) have chronic inspiratory muscle fatigue was tested in an effectiveness trial in which negative pressure ventilation (NPV) was used to produce inspiratory muscle rest. In a double-blind study 184 patients with severe COPD were randomly allocated active or sham NPV treatment for a 12-week period of home use. The distance walked in a 6 min walk test was the primary outcome variable. Secondary outcome measures were cycle exercise endurance time, severity of dyspnoea, quality of life, arterial blood gas tensions, and respiratory muscle strength. The percentage reduction in amplitude of the diaphragmatic electromyographic signal multiplied by hours of NPV was used to reflect the dose of NPV so we could examine dose-response relations. Analysis was based on intention to treat. We found no evidence of a clinically or statistically significant difference in any outcome measure between active and sham groups. No dose-response relation was observed. Moreover, the intervention was poorly accepted despite substantial clinical support. We conclude that NPV as used in this study is difficult to apply and ineffective when used with the aim of resting the respiratory muscles in patients with stable COPD.

Clinical trials have demonstrated a prophylactic role for aspirin in myocardial infarction and in unstable angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) is the first prospective study of aspirin in stable angina. 2035 patients were randomised double-blind to treatment with aspirin 75 mg daily or placebo. All patients were treated with sotalol for control of symptoms. The median duration of follow-up was 50 months. Compared with the placebo+sotalol group, the aspirin+sotalol group had a 34% (81 vs 124 patients) reduction in primary outcome events (myocardial infarction and sudden death; 95% confidence interval 24-49%; p = 0.003) and the reduction observed in secondary outcome events (vascular events, vascular death, all cause mortality, stroke) ranged from 22% to 32%. Treatment withdrawal caused by adverse events occurred in 109 patients in the aspirin+sotalol group and 100 in patients in the placebo+sotalol group; major bleeds, including haemorrhagic stroke, occurred in 20 and 13 patients, respectively (not significant). The addition of a low dose of aspirin to sotalol treatment showed significant benefit in terms of cardiovascular events, including a significant reduction in the incidence of first myocardial infarction in patients with symptoms of stable angina pectoris.

Although exogenous surfactants are of known efficacy in the prevention and treatment of respiratory distress syndrome (RDS), questions remain about the best regimens. During 1990-91, 6774 babies were recruited to an international multicentre trial to assess when administration of Exosurf, a synthetic surfactant, should be started and how often it should be given. The clinical outcome is known for 6757 (99.7%) infants. 2690 babies, judged to be at high risk of RDS when less than 2 hours of age, were randomly allocated to either early administration or delayed selective administration; 96% versus 73% received surfactant, at median ages of 118 and 182 min. The risk of death or dependence on extra oxygen at the expected date of delivery was 16% (95% CI 25% to 7%) lower among infants allocated early administration. Early administration was also associated with a 32% lower risk of pneumothorax. These 2690 infants were further randomised in a factorial design to either two doses of surfactant 12 hours apart, or the option of third and fourth doses at 12-36 hour intervals if signs of RDS persisted or recurred. 4067 other infants who later developed RDS were also recruited to this comparison, giving a total of 3376 infants allocated up-to-four doses (of whom, 45% received more than two) and 3381 allocated two doses. The outcome was similar in the two groups in respect of death, long-term oxygen dependence, and other major morbidity, even in secondary analyses restricted to infants who met the criteria for additional administration. There were more reports of poorly tolerated administration in the up-to-four doses group but no clear increase in serious morbidity, such as pulmonary haemorrhage. The OSIRIS trial suggests that early administration of surfactant to an estimated 32 babies, when compared with treatment of established RDS, would prevent 1 baby from dying and another from being dependent on extra oxygen long-term, but would entail the additional use of surfactant in 8 of these babies. It provides no evidence that a regimen including the option of third and fourth doses when signs of RDS persist or recur is clinically superior to a regimen of two doses.

We have done a randomised controlled trial to assess the effect on primary management and outcome of routine doppler ultrasound examinations of the umbilical and uterine arteries during pregnancy. Over 9 months, 2600 women with singleton pregnancies were recruited from a general obstetric population. Of 2475 women who delivered in hospital after 20 weeks' gestation, 1246 had been allocated at random to receive standard antenatal care with routine doppler examinations. The first doppler ultrasound was done at 19-22 weeks' gestation, and thereafter examinations were monthly if the pregnancy was considered high risk (192) or once at 32 weeks if considered low risk (1054). The control group of 1229 women received standard, antenatal care without doppler ultrasonography. The study groups did not differ in number of antenatal admissions or cardiotocographs, gestational age at delivery, method of delivery, frequency of deliveries with fetal distress, or need for resuscitation or admission to the neonatal intensive care unit. More perinatal deaths occurred in the doppler group (17 vs 7, relative risk 2.4, 95% Cl 1.00-5.76), but only 1 of 11 normally formed stillbirths and none of the 4 normally formed neonatal deaths after 24 weeks' gestation had an abnormal umbilical-artery doppler examination. We did not demonstrate any improvement in neonatal outcome by routine doppler ultrasound screening of a general obstetric population.

We compared the efficacy of amphotericin B and pentamidine isethionate in a prospective randomised trial in 120 uncomplicated and parasitologically confirmed cases of antimony-unresponsive kala-azar. Doses were twenty intramuscular injections of pentamidine 4 mg/kg on alternate days or fourteen definitive doses of amphotericin 0.5 mg/kg infused in 5% dextrose on alternate days. 48 (80%) patients given pentamidine showed initial cure and 46 (77%) showed definitive cure compared with 60 (100%) and 59 (98%) cases, respectively, on amphotericin (p < 0.001). Amphotericin also brought about quicker abatement of fever and more complete spleen regression.

Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or artemether (34). Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular artemether given over 5 days. Oral artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria.

We have compared three methods of prenatal diagnosis in two large obstetric centres in Denmark. Women were randomly assigned transabdominal (TA) chorionic villus sampling (CVS), transcervical (TC) CVS, or second-trimester amniocentesis (AC); women at high genetic risk were randomised between the two CVS groups only. Analysis of 45 epidemiological variables showed the three procedure groups to be similar at enrollment. All women were followed up until completion of pregnancy. Among 3079 women at low genetic risk total fetal loss rates were 10.9% for TC CVS, 6.3% for TA CVS, and 6.4% for AC (p < 0.001). More women had bleeding after the procedure in the CVS groups (p < 0.001), whereas more amniotic fluid leakage (p < 0.001) was reported after AC. No uterine infections occurred in any group. No case of oromandibular-limb abnormality was seen in the CVS groups, but 1 child in the AC group had aplasia of the right hand. The two CVS approaches were compared among 2882 women at low and high genetic risk who were found to have cytogenetically normal fetuses. Rates of unintentional loss after the procedure were 7.7% for TC CVS and 3.7% for TA CVS (p < 0.001; 95% Cl of difference 2.3-5.8%). At baseline ultrasound scanning after establishment of optimum sampling conditions, more TC than TA procedures (p < 0.001) were judged not to be feasible. We found that TA CVS allows better access to the placental site than TC sampling, is an easier skill to acquire, and has the potential that more villi can be aspirated when needed. The risk of fetal loss is similar after TA CVS and AC. However, losses after AC are at a later stage and are therefore more distressing. TA procedures remain the first choice for prenatal diagnosis. Since, in our hands, TC sampling carries a greater risk to the fetus, we have abandoned TC CVS in our two study centres.

Early clinical studies of coronary and peripheral laser angioplasty showed that arterial occlusions could be recanalised by continuous-wave lasers delivered with contact probes and by pulsed lasers applied with multifibre catheters. However, whether laser-assisted angioplasty improves success rates in reopening occlusions and in long-term patency rates is unclear. We have compared the primary recanalisation and long-term patency rates after laser-assisted and conventional percutaneous transluminal angioplasty (PTA) of femoropopliteal artery occlusions in 116 consecutive symptomatic patients (excimer laser 37, Nd:YAG laser 40, PTA 39). Primary recanalisation was achieved in 81 patients (70%). The primary recanalisation rate achieved with the excimer laser was significantly lower than that with the Nd:YAG laser (49% vs 78%, p < 0.01) or with PTA (82%, p < 0.003). The overall angiographic recanalisation rate (primary and secondary recanalisation) after laser and PTA was 89%. After 3 months, clinical improvement was recorded in 76% of patients. Clinical long-term results were available in 94 (91%), and angiographic long-term results in 77 (75%), of 103 successfully recanalised patients. Life-table analysis of the long-term results revealed no significant difference of the restenosis rate between the three treatment groups. The 12-month patency rate was 60% as assessed clinically and 39% as judged by angiography. Primary and secondary recanalisation rates and long-term patency rates were significantly correlated with length of the occlusion. Our results suggest that PTA of femoropopliteal artery occlusions is only indicated if the occlusion is short (< 8 cm) and that laser-assisted angioplasty should only be used after failure of conventional PTA.

An association between raised renin levels and myocardial infarction has been reported. We studied the effects of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on the development of myocardial infarction and unstable angina in 6797 patients with ejection fractions < or = 0.35 enrolled into the two Studies of Left Ventricular Dysfunction (SOLVD) trials. Patients were randomly assigned to placebo (n = 3401) or enalapril (n = 3396) at doses of 2.5-20 mg per day in two concurrent double-blind trials with the same protocol. Patients with heart failure entered the treatment trial (n = 2569) and those without heart failure entered the prevention trial (n = 4228). Follow-up averaged 40 months. In each trial there were significant reductions in the number of patients developing myocardial infarction (treatment trial: 158 placebo vs 127 enalapril, p < 0.02; prevention trial: 204 vs 161 p < 0.01) or unstable angina (240 vs 187 p < 0.001; 355 vs 312, p < 0.05). Combined, there were 362 placebo group patients with myocardial infarction compared with 288 in the enalapril group (risk reduction 23%, 95% CI 11-34%; p < 0.001). 595 placebo group patients developed unstable angina compared with 499 in the enalapril group (risk reduction 20%, 95% CI 9-29%, p < 0.001). There was also a reduction in cardiac deaths (711 placebo, 615 enalapril; p < 0.003), so that the reduction in the combined endpoint of deaths, myocardial infarction, and unstable angina was highly significant (20% risk reduction, 95% CI 14-26%; p < 0.0001). Enalapril treatment significantly reduced myocardial infarction, unstable angina, and cardiac mortality in patients with low ejection fractions.