Preterm, low-birthweight (LBW) newborn infants are at high risk of neonatal mortality and morbidity and need early referral for special paediatric care. In developing countries, birthweight and gestational age often cannot be measured and a practical screening tool based on surrogate neonatal body measurements to identify high-risk infants would be very useful. We studied a consecutive series of 843 singleton infants born at a referral hospital in Addis Ababa, Ethiopia. Gestational age, birthweight, and four body measurements (chest, head, and mid-arm circumferences and length) were accurately recorded. We randomly divided the series into equal-sized training and validation groups. In the training group, we used a recursive partitioning technique to develop a simple predictive algorithm--infants were classified as high risk if head circumference was 31 cm or less or if chest circumference was 30 cm or less, and were classified as low risk otherwise. When tested in the validation group, this algorithm had sensitivity, specificity, and negative predictive value for prediction of preterm and LBW births above 90%. Thus, neonatal body measurements can be combined into a pragmatic, accurate screening tool suitable for clinical use in developing countries.

In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.

We did a prospective study of women with singleton viable pregnancies at 10-13 weeks' gestation who requested first-trimester fetal karyotyping because of advanced maternal age, parental anxiety, or family history of chromosomal abnormality. Women were counselled as to the available options of non-invasive screening or invasive testing by mid-trimester amniocentesis, early amniocentesis (EA), or chorionic villus sampling (CVS), or randomisation to EA or CVS at 10-13 weeks. EA was done in 731 patients (493 by choice and 238 by randomisation) and CVS in 570 (320 by choice and 250 by randomisation). Both procedures were done by transabdominal ultrasound-guided insertion of a 20-gauge needle. The rate of successful sampling was the same for both procedures (97.5%). Spontaneous loss (intrauterine or neonatal death) was significantly higher after EA (total group mean = 5.3%, 95% CI 3.8-7.2; randomised subgroup mean = 5.9%, 3.3-9.7) than after CVS (total group: mean = 2.3%, 1.2-3.9; randomised subgroup: mean = 1.2%, 0.3-3.5). The gestation at delivery and birthweight of the infants after EA and CVS were similar. In the EA group the incidence of talipes equinovarus (1.63%), was higher than in the CVS group (0.56%), but this difference was not significant.

Studies in the USA and Japan have shown that tacrolimus (FK506) is a potent immunosuppressant. To compare the efficacy and safety of tacrolimus-based and conventional cyclosporin-based immunosuppressive regimens we recruited 545 liver transplant recipients from eight European centres into a randomised open trial. Analysis of the data at 12 months post-transplant showed that tacrolimus was associated with a significant reduction in acute, refractory acute, and chronic rejection episodes. The rates were, for acute rejection, tacrolimus 40.5% vs 49.8% cyclosporin (p = 0.040; absolute difference 9.3% [95% CI 0.9-17.8%]). For refractory acute and chronic rejections the comparisons were 0.8% vs 5.3% (p = 0.005) and 1.5% vs 5.3% (p = 0.032). There results were seen despite significantly lower corticosteroid usage. The incidence of infection was also lower in patients receiving tacrolimus. Patient and graft survival rates were not significantly different (tacrolimus 82.9% and 77.5%; cyclosporin 77.5% and 72.6%). Safety data were comparable--the most serious events being renal impairment, disturbances of glucose metabolism, and neurological complications--but these events were more common in the tacrolimus group. In this trial tacrolimus had advantages over cyclosporin in respect of lower rejection rates, even though less concurrent immunosuppression was administered.

The risk of blood-borne diseases has substantially increased the use of autologous blood transfusion. Many autologous donors, however, still need homologous transfusions. To find out whether recombinant erythropoietin (rhEPO) reduces requirements for homologous blood transfusion, we carried out a randomised, controlled trial, in which patients were stratified according to blood volume. We studied 95 autologous blood donors undergoing elective hip surgery. 50 patients were randomly assigned 500 U/kg rhEPO subcutaneously twice a week for 3 weeks, and 45 patients received no treatment (control group). The patients each donated two units of blood before surgery. Only 5 (10%) rhEPO-treated patients received homologous transfusions compared with 16 (36%) controls (p < 0.01). rhEPO was most useful in patients with a blood volume below 4 L and an estimated blood loss below 2 L or with a blood volume of 4-5 L and blood loss of 1-2 L. Continued administration of rhEPO caused no further increase in reticulocyte counts after the fourth injection, which was accompanied by a pronounced depletion of storage iron. rhEPO treatment had no effect on renal function, platelet count, or blood pressure. Subcutaneous rhEPO is an effective and safe way to reduce exposure to homologous blood in autologous donors. Its use can be restricted to a subpopulation of autologous blood donors, which improves the cost-effectiveness of this expensive approach.

Efficacy of the Haemophilus influenzae type b (Hib) conjugate vaccine PRP-T (Pasteur-Merieux) was evaluated in a controlled community intervention study in the Oxford region, UK. PRP-T was offered to infants from May 1, 1991 in three of the region's eight districts and from July 1, 1991, in a fourth district. It was given by separate injection in addition to the standard diphtheria, tetanus, and pertussis vaccine according to an accelerated 2, 3, and 4 month schedule without a booster dose in the second year of life. By October 1, 1992, more than 90% of infants in vaccine districts had received at least one dose of PRP-T. None of the infants given three doses had developed Hib infection, whereas 11 infections occurred in the control population (vaccine efficacy 100%, 95% CI 80-100%). Intention-to-treat analysis also showed a high estimate of efficacy for the vaccine (90%, 50-99%). Follow-up of study children until November 1, 1993, has shown only 1 vaccine failure in an infant, and no invasive infections in those older than 1 year (average age 22 months). PRP-T vaccine had high protective efficacy with an accelerated immunisation schedule. Furthermore, the vaccine appears to remain protective through the second year of life without a booster dose. These findings provide encouragement for use of PRP-T in the Expanded Programme of Immunisation.

In developing countries, the age at which breastfed infants are first given complementary foods is of public health importance because of the risk of diarrhoeal disease from contaminated weaning foods, and the potential risk of growth faltering if foods are inappropriately delayed. To evaluate whether there are any advantage of complementary feeding prior to 6 months, low-income primiparous mothers who had exclusively breastfed for 4 months were randomly assigned to one of 3 groups: continued exclusive breastfeeding to 6 months (EBF) (n = 50); introduction of complementary foods at 4 months with ad libitum nursing from 4-6 months (SF) (n = 47); and introduction of complementary foods at 4 months, with maintenance of baseline nursing frequency from 4-6 months (SF-M) (n = 44). Baby foods in jars were provided to the SF and SF-M groups from 4 to 6 months. Subjects were visited weekly and provided with lactation guidance; at 4, 5, and 6 months measurements were made of infant intake and breast milk composition. At 4 months, breast milk intake averaged 797 (139) g per day (no difference among groups). Between 4 and 6 months, breast milk intake was unchanged in EBF infants (+6) but decreased in the SF (-103), and SF-M (-62) groups (p < 0.001). Change in total energy intake (including solid foods) and infant weight and length gain did not differ significantly between groups. Weight and length gain from 4-6 months were comparable to those of breastfed infants in an affluent USA population. The results indicate that breastfed infants self-regulate their total energy intake when other foods are introduced. As a result, there is no advantage in introducing complementary foods before 6 months in this population, whereas there may be disadvantages if there is increased exposure to contaminated weaning foods.

A beneficial effect of periodic vitamin A supplementation on childhood mortality has been demonstrated, but the effect on morbidity is less clear. We investigated the effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections (ALRI) in children from northeastern Brazil in a randomised, double-blind, placebo-controlled community trial. 1240 children aged 6-48 months were assigned vitamin A or placebo every 4 months for 1 year. They were followed up at home three times a week, and data about the occurrence and severity of diarrhoea and ALRI were collected. Any child with cough and respiratory rate above 40 breaths per min was visited by a paediatrician. The overall incidence of diarrhoea episodes was significantly lower in the vitamin-A-supplemented group than in the placebo group (18.42 vs 19.58 x 10(-3) child-days; rate ratio 0.94 [95% Cl 0.90-0.98]). The benefit of supplementation was greater as regards severe episodes of diarrhoea; the incidence was 20% lower in the vitamin A group than in the placebo group (rate ratio 0.80 [0.65-0.98]). With the standard definition of diarrhoea (> or = 3 liquid or semi-liquid stools in 24 h) the effect of vitamin A on mean daily prevalence did not reach significance, but as the definition of diarrhoea was made more stringent (increasing number of stools per day), a significant benefit became apparent, reaching for diarrhoea with 6 or more liquid or semi-liquid stools in 24 h a 23% lower prevalence. We found no effect of vitamin A supplementation on the incidence of ALRI. The reduction in severity of diarrhoea may be the most important factor in the lowering of mortality by vitamin A supplementation.

Guidelines on asthma management recommend that in patients who still have symptoms on treatment with low-dose inhaled corticosteroids the first step should be an increase in inhaled corticosteroid dose. The addition of long-acting inhaled beta 2-adrenoceptor agonists is another option. We have compared these two strategies in a randomised, double-blind, parallel-group trial. We studied 429 adult asthmatic patients who still had symptoms despite maintenance treatment with 200 micrograms twice daily inhaled beclomethasone dipropionate (BDP). 3 did not provide verifiable data. Of the others, 220 were assigned salmeterol xinafoate (50 micrograms twice daily) plus BDP and 206 were assigned higher-dose BDP (500 micrograms twice daily) for 6 months. The mean morning peak expiratory flow increased from baseline in both groups, but the increase was greater in the salmeterol/BDP group than in the higher-dose BDP group at all time points (differences 16-21 L/min, p < 0.05). Mean evening PEF also increased with salmeterol/BDP but not with higher-dose BDP. There were significant differences in favour of salmeterol/BDP in diurnal variation of PEF (all time points) and in use of rescue bronchodilator (salbutamol) and daytime and night-time symptoms (some time points). There was no significant difference between the groups in adverse effects or exacerbations of asthma, indicating that in this group of patients regular beta 2-agonist therapy was not associated with any risk of deteriorating asthma control over 6 months. This study suggests a need for a flexible approach to asthma management.

The effect of oral aspirin on the healing rate of chronic venous leg ulcers was compared with that of placebo in a double-blind randomised trial. 20 subjects with chronic venous leg ulcers were randomised to daily enteric-coated aspirin 300 mg or placebo, and standardised compression bandaging. 4 months of treatment achieved ulcer healing in 38% of the patients receiving aspirin compared with 0% of those receiving placebo (p < 0.007). 52% of the aspirin-treated group showed significant reduction in ulcer size compared with 26% of placebo recipients (p < 0.007). Reduction in ulcer surface area was significantly better in the aspirin-treated group at 2 (p < 0.01) and 4 months (p < 0.002) compared with that in the placebo group.

The safety and immunogenicity of a new virosome influenza vaccine was compared to commercial whole-virus vaccine and subunit vaccine in elderly people. The virosome vaccine was made by extracting the haemagglutinin from influenza virus and incorporating it into the membrane of liposomes composed of phosphatidylcholine (PC) and phosphatidylethanolamine (PE). 126 residents of a nursing home, aged 63-102, were randomised to receive one of the vaccines. All three were well tolerated and caused a significant rise in the geometric mean anti-haemagglutinin inhibiting (HAI) antibody titre to the 3 vaccine components (H1N1 Singapore, H3N2 Beijing, and B/Yamagata). The virosome formulation caused the highest geometric mean titres in addition to significantly (p = 0.039-0.0016) higher rates of more than four-fold or more titre rises to all 3 vaccine components. The percentage of those immunised who achieved protective levels of antibody (HAI > or = 40) was significantly (p = 0.035-0.0017) higher for the H1N1 and B/Yamagata strains following immunisation with virosome formulation. Participants with non-protective baseline titres to the H1N1 or B/Yamagata strains were more likely (p = 0.0049-0.006) to achieve protective levels of antibodies after immunisation with the virosome vaccine. Immunisation with the virosome formulation did not result in a significant rise in anti-PC or anti-PE antibodies.

Previous small clinical trials have suggested that treatment with nitric oxide donors in suspected myocardial infarction can reduce mortality by 30-35%. To confirm this finding in a large-scale trial, we compared molsidomine and its active metabolite linsidomine (a nitric oxide donor) with placebo in 4017 patients with acute myocardial infarction. In our trial, patients without signs of overt heart failure (Killip III/IV) were randomly assigned in a double-blind design within 24 h of symptom onset to receive linsidomine 1 mg/h intravenously for 48 h, followed by 16 mg molsidomine by mouth daily for 12 days (n = 2007), or an identical placebo (n = 2010). All other treatments could be used at the responsible physician's discretion with the exception of systematic vasodilator treatment. The molsidomine and placebo groups showed similar all-cause 35-day mortality (168 [8.4%] vs 176 [8.8%] deaths, p = 0.66), and adjustment for baseline variables in a Cox model had no effect. Similarly, we found no difference for long-term mortality (mean follow-up 13 months; 294 [14.7%] vs 285 [14.2%] deaths, p = 0.67). The two groups showed similar frequencies of major and minor adverse events; only headache was significantly more common in the molsidomine group. Changes in treatment practices and the lower risk profile of our study subjects than of participants in previous trials may explain the results. It is still not clear whether nitric oxide donors can improve survival in higher-risk myocardial infarction patients.

Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.

The efficacy of antiarrhythmic drugs for terminating sustained ventricular tachycardia (VT) has been disappointing. Lignocaine is the traditional drug but it is not very effective. Sotalol, one of the most effective drugs in suppressing spontaneous or induced VT, should theoretically be useful in this setting. We have compared lignocaine with sotalol for the acute termination of spontaneous sustained VT not causing cardiac arrest in 33 patients (26 males, 7 females, aged 21-90) whose underlying heart disease was old myocardial infarction (28), acute myocardial infarction (2), dilated cardiomyopathy (1), or idiopathic cardiomyopathy (2). Left-ventricular ejection fraction was 35% (range 18-76%). Patients were randomly allocated in a double-blind fashion to lignocaine 100 mg (n = 17) or sotalol 100 mg (n = 16) given intravenously over 5 min. Those with persistent VT 15 min after onset of administration of the first drug were crossed over to the other drug. Sotalol was significantly more effective than lignocaine whether analysed on an intention-to-treat basis (69% vs 18%; 95% confidence interval for absolute difference of 51% 22-80%, p = 0.003) or by analysis limited to the 31 patients with subsequent electrophysiologically proven VT (69% vs 20%). 1 patient in each group required cardioversion after the first drug. Tachycardia persisted in 14 patients in the lignocaine group and 4 in the sotalol group after 15 min. Tachycardia ceased in 7 (50%) patients who crossed over to sotalol, and in 1 patient who crossed over to lignocaine. There was 1 death in each group after the first drug and 1 death after both drugs. We conclude that sotalol was superior to lignocaine for the acute termination of sustained VT. The incidence of adverse effects was similar for the two drugs.

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in children. Paralysis of respiratory muscles causes a decrease in forced vital capacity (FVC) from age 12 years, and death occurs between 20 and 25 years old and is usually related to respiratory insufficiency. Uncontrolled studies suggest that early home use of nasal intermittent positive-pressure ventilation (NIPPV) in DMD patients free of respiratory failure could limit progression of the restrictive syndrome and therefore improve survival because efficacy of preventive NIPPV has not been demonstrated in a controlled trial, we undertook a randomised multicentre study in which 70 patients with DMD were included. Patients were free of daytime respiratory failure and FVC was between 20 and 50% of predicted values. At least 6 h of nocturnal NIPPV (n = 35) was compared with conventional treatment (n = 35). During a mean follow-up of 52 months, 10 patients died, 8 in the NIPPV group and 2 in the control group (p = 0.05, log-rank test). No differences were observed between the two groups for occurrence of hypercapnia, decrease of FVC below 20% of initial values, or use of necessary mechanical ventilation. Preventive NIPPV did not improve respiratory handicap and reduced survival of DMD patients. Use of NIPPV for preventive purposes should be avoided in patients with FVC between 20 and 50% of predicted values.