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Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Donéguébougou and surrounding villages in Mali. We recruited 18–35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 105 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov, number NCT01988636. Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three [7%] people in the vaccine group vs four [9%] in the placebo group) followed by fatigue (one [2%] person in the placebo group), fever (one [2%] person in the placebo group), and myalgia (one [2%] person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313–0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528–0·918) by proportional analysis (p=0·006). PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season. US National Institutes of Health Intramural Research Program, Sanaria.

Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease. Combining these medications may provide additional benefits. To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting beta(2)-agonist combination therapy. In this 12-week, randomized, double-blind, parallel-group, multicenter study, after a 2-week run-in, 660 subjects (75% male; mean age, 62 yr; FEV(1), 1.1 L; 38% predicted normal), 40 years of age or older, received tiotropium (18 microg once daily) plus either budesonide/formoterol (320/9 microg) (n = 329) or placebo (n = 331) twice daily. Clinic predose (primary outcome) and postdose FEV(1), predose and postdose forced vital capacity and inspiratory capacity, and health status were measured. Other outcomes included daily measurements taken at home (pre- and postdose morning FEV(1) and peak expiratory flow, morning symptoms and activities, and morning reliever use), severe exacerbations, and tolerability. Over the treatment period, budesonide/formoterol plus tiotropium significantly increased predose FEV(1) by 6% (65 ml) and postdose by 11% (123 and 131 ml at 5 and 60 min postdose, respectively) versus tiotropium alone (both P < 0.001). Other outcomes all significantly improved with budesonide/formoterol plus tiotropium versus tiotropium alone. The number of severe exacerbations decreased by 62% (rate ratio, 0.38; 95% confidence interval, 0.25-0.57; P < 0.001). Both treatments were well tolerated. In patients with chronic obstructive pulmonary disease, budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function, health status, morning symptoms and activities, and reduces severe exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT00496470).

Background In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting β2 agonists (SABAs) on demand. Objective The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. Methods Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg)  + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Results After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI −10.3 to −3.0) and 5.4% (−8.9 to −1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; −2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. Conclusions The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma.

Health workers' malaria case-management practices often differ from national guidelines. We assessed whether text-message reminders sent to health workers' mobile phones could improve and maintain their adherence to treatment guidelines for outpatient paediatric malaria in Kenya. From March 6, 2009, to May 31, 2010, we did a cluster-randomised controlled trial at 107 rural health facilities in 11 districts in coastal and western Kenya. With a computer-generated sequence, health facilities were randomly allocated to either the intervention group, in which all health workers received text messages on their personal mobile phones on malaria case-management for 6 months, or the control group, in which health workers did not receive any text messages. Health workers were not masked to the intervention, although patients were unaware of whether they were in an intervention or control facility. The primary outcome was correct management with artemether-lumefantrine, defined as a dichotomous composite indicator of treatment, dispensing, and counselling tasks concordant with Kenyan national guidelines. The primary analysis was by intention to treat. The trial is registered with Current Controlled Trials, ISRCTN72328636. 119 health workers received the intervention. Case-management practices were assessed for 2269 children who needed treatment (1157 in the intervention group and 1112 in the control group). Intention-to-treat analysis showed that correct artemether-lumefantrine management improved by 23·7 percentage-points (95% CI 7·6–40·0; p=0·004) immediately after intervention and by 24·5 percentage-points (8·1–41·0; p=0·003) 6 months later. In resource-limited settings, malaria control programmes should consider use of text messaging to improve health workers' case-management practices. The Wellcome Trust.

Abstract Background and aims We aimed to examine, for the first time, the effect of cannabidiol (CBD) and palmitoylethanolamide (PEA) on the permeability of the human gastrointestinal tract in vitro, ex vivo, and in vivo. Methods Flux measurements of fluorescein-labeled dextrans 10 (FD10) and fluorescein-labeled dextrans 4 (FD4) dextran across Caco-2 cultures treated for 24 hours with interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα) (10 ng·mL−1) were measured, with or without the presence of CBD and PEA. Mechanisms were investigated using cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), transient receptor potential vanilloid 1 (TRPV1), and proliferator activated receptors (PPAR) antagonists and protein kinase A (PKA), nitric oxide synthase, phosphoinositide 3-kinases, extracellular signal-regulated kinases (MEK/ERK), adenylyl cyclase, and protein kinase C (PKC) inhibitors. Human colonic mucosal samples collected from bowel resections were treated as previously stated. The receptors TRPV1, PPARα, PPARδ, PPARγ, CB1, CB2, G-coupled protein receptor 55 (GPR55), G-coupled protein receptor 119 (GPR119), and claudins-1, -2, -3, -4, -5, -7, and -8 mRNA were measured using multiplex. Aquaporin 3 and 4 were measured using enzyme-linked immunosorbent assay (ELISA). A randomized, double-blind, controlled-trial assessed the effect of PEA or CBD on the absorption of lactulose and mannitol in humans taking 600 mg of aspirin. Urinary concentrations of these sugars were measured using liquid chromatography mass spectrometry. Results In vitro, PEA, and CBD decreased the inflammation-induced flux of dextrans (P < 0.0001), sensitive to PPARα and CB1 antagonism, respectively. Both PEA and CBD were prevented by PKA, MEK/ERK, and adenylyl cyclase inhibition (P < 0.001). In human mucosa, inflammation decreased claudin-5 mRNA, which was prevented by CBD (P < 0.05). Palmitoylethanolamide and cannabidiol prevented an inflammation-induced fall in TRPV1 and increase in PPARα transcription (P < 0.0001). In vivo, aspirin caused an increase in the absorption of lactulose and mannitol, which were reduced by PEA or CBD (P < 0.001). Conclusion Cannabidiol and palmitoylethanolamide reduce permeability in the human colon. These findings have implications in disorders associated with increased gut permeability, such as inflammatory bowel disease.

The contributions of as-needed inhaled corticosteroids and long-acting β2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting β2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy. We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 μg and 4·5 μg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications—terbutaline (0·4 mg), formoterol (4·5 μg), or budesonide-formoterol (160 μg and 4·5 μg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more. Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0·0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0·0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0·67 [95% CI 0·56–0·80; p<0·0001]; budesonide-formoterol versus terbutaline 0·52 [0·44–0·62; p<0·0001]; formoterol versus terbutaline 0·78 [0·67–0·91; p=0·0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated. Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5–8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554–555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference −1·2 mm Hg, 95% CI −2·3 to −0·1; p=0·030) and valsartan 320 mg/day (−4·4 mm Hg, −5·4 to −3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30–36% of participants in each group. Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. Forest Research Institute.

Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens.

Background QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. Methods This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety. Results Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: –0.69 units; 95% CI −2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). Conclusions QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. Trial registration number NCT01120717.

Asthma exacerbations during pregnancy are common and can be associated with substantial maternal and fetal morbidity. Treatment decisions based on sputum eosinophil counts reduce exacerbations in non-pregnant women with asthma, but results with the fraction of exhaled nitric oxide (F ENO) to guide management are equivocal. We tested the hypothesis that a management algorithm for asthma in pregnancy based on F ENO and symptoms would reduce asthma exacerbations. We undertook a double-blind, parallel-group, controlled trial in two antenatal clinics in Australia. 220 pregnant, non-smoking women with asthma were randomly assigned, by a computer-generated random number list, before 22 weeks’ gestation to treatment adjustment at monthly visits by an algorithm using clinical symptoms (control group) or F ENO concentrations (active intervention group) used to uptitrate (F ENO >29 ppb) or downtitrate (F ENO <16 ppb) inhaled corticosteroid dose. Participants, caregivers, and outcome assessors were masked to group assignment. Longacting β2 agonist and minimum dose inhaled corticosteroid were used to treat symptoms when F ENO was not increased. The primary outcome was total asthma exacerbations (moderate and severe). Analysis was by intention to treat. This study is registered with the Australian and New Zealand Clinical Trials Registry, number 12607000561482. 111 women were randomly assigned to the F ENO group (100 completed) and 109 to the control group (103 completed). The exacerbation rate was lower in the F ENO group than in the control group (0·288 vs 0·615 exacerbations per pregnancy; incidence rate ratio 0·496, 95% CI 0·325–0·755; p=0·001). The number needed to treat was 6. In the F ENO group, quality of life was improved (score on short form 12 mental summary was 56·9 [95% CI 50·2–59·3] in F ENO group vs 54·2 [46·1–57·6] in control group; p=0·037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p=0·046). Asthma exacerbations during pregnancy can be significantly reduced with a validated F ENO-based treatment algorithm. National Health and Medical Research Council of Australia.