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Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival., Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140)., Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001)., Interpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial., Funding: UK National Institute for Health Research, Health Technology Assessment Programme., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Routine immunisation of infants in The Gambia with a Haemophilus influenzae type b (Hib) polysaccharide-tetanus toxoid conjugate vaccine began in May, 1997. We investigated the effectiveness of the vaccine when delivered through the expanded programme on immunisation and the effect of national immunisation on incidence of Hib disease., Methods: Surveillance for Hib disease was maintained in the western half of The Gambia using standard methods with an emphasis on meningitis. We estimated vaccine efficacy using the case control method, and vaccine coverage and population denominators for incidence rates using a cluster sample survey. Prevalence of Hib carriage in a sample of 1-2-year old children attending health centres for vaccination was ascertained with oropharyngeal swabs plated onto antiserum agar., Findings: Between May, 1997, and April, 2002, a total of 5984 children were examined for possible Hib infections. 49 children had Hib disease, 36 of whom had meningitis. The annual incidence rates of Hib meningitis before any use of the vaccine (1990-93) dropped from over 200 per 100,000 children aged younger than 1 year to none per 100,000 in 2002, and from 60 to no cases per 100,000 in children younger than 5 years. The prevalence of Hib carriage decreased from 12% to 0.25% (p<0.0001). Two doses of vaccine were needed for direct protection from Hib disease (vaccine efficacy 94%, 95% CI 62-99). Since most children received a protective dose after the age of greatest disease risk, indirect effects were important in reducing disease incidence., Interpretation: The Gambian Hib immunisation programme reduced the occurrence of Hib disease despite irregular vaccine supply. The effect of the programme in The Gambia has important implications for the introduction of the vaccine into routine immunisation programmes of other developing countries.

Background: Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children., Methods: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat., Findings: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo., Interpretation: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

Background: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia., Methods: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol., Findings: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037)., Interpretation: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

Background: Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment., Methods: We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared., Findings: The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment., Interpretation: The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.

Metabolic and serum changes during steady-state homozygous sickle cell (SS) disease are consistent with an acute-phase response and raise the possibility that inflammation occurs in SS disease even during the steady state. To test this hypothesis, we measured concentrations of acute phase reactants in patients with SS disease, in patients with sickle cell haemoglobin C (SC) disease, and in normal (AA) control subjects. The concentrations of C-reactive protein and serum amyloid A were increased above 10 mg/L and 5 mg/L, respectively (our definition of an acute-phase response) in 18% (26/143) of subjects with SS disease even when they were symptom free, in 17% (6/35) of subjects with SC disease, and in 1% (1/80) of AA controls (p < 0.001). We suggest that subclinical vaso-occlusion may generate a covert inflammatory response and that the cytokine mediators of this response may contribute to the metabolic abnormalities and growth failure in sickle cell disease.

Serum concentrations of serum amyloid A protein, the high-density-lipoprotein-associated tissue amyloid A precursor, were determined in 29 diabetic patients receiving insulin by subcutaneous injection and in 50 receiving subcutaneous infusion pump therapy. Insulin delivered by continuous subcutaneous pumps stimulated serum amyloid A production to levels nearly six times those in normal subjects, nearly twice as much as insulin given by subcutaneous injection. 85% of patients with serum amyloid A levels greater than or equal to 10(4) ng/ml were being treated with insulin pump therapy. The relation between insulin aggregation and amyloid A in diabetes was evaluated in 1 patient; treatment with syringe-aggregated insulin resulted in a nearly 300% increase in serum amyloid A levels. The use of high-potency non-aggregating insulins in the pump treatment of type I diabetic patients may be necessary for optimum therapy.

Rectal biopsy in 190 inpatients at a leprosy hospital in the Highlands of Papua New Guinea disclosed 16 patients with secondary amyloidosis. This represented 20% of the patients who had had polar lepromatous leprosy (L.L.) for more than 2 years. Patients with amyloidosis characteristically had either a history of recurrent attacks of erythema nodosum leprosum (E.NH) reactions or chronic trophic ulcers. Levels of the serum component (protein SAA) antigenically related to the amyloid fibril protein AA were monitored, at varying intervals for three months, in lepromatous patients with E.N.L. reaction. The SAA levels rose during E.N.L. reactions in parallel with the neutrophil count. SAA occurred with greatest frequency among patients with LH, while most non-lepromatous patients with detectable SAA had chronic trophic ulcers. The correlation between raised neutrophil count and elevated SAA concentration, observed in this and other studies, suggests that neutrophils are associated with the production of SAA.