ObjectivesThe aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.MethodsPatients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.ResultsAcross 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1–29.9%, OKZ=32.5–60.7%; ACR50: PBO=1.3–4.9%, OKZ=11.5–33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.ConclusionsOKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.Trial register number:NCT01242488.

No abstract

Maternal milk, a main source of nutrition for neonates in early life, has attracted attention. An increasing number of studies have found that maternal milk has a high microbial diversity, as well as factors that might influence this diversity. However, there is a lack of knowledge regarding the effects of host diet and phylogeny on maternal milk microbes and the contribution of the maternal milk microbiota to the neonatal gut microbiota. Here, we analyzed the maternal milk and fecal microbiota of nine species (lion, dog, panda, human, mouse, rhesus macaque, cow, goat, and rabbit) of mammals of three type groups (herbivore, omnivore, and carnivore) using 16S rRNA amplicon sequencing. Our study provided evidence of host diet and phylogeny on the maternal milk microbiota. Moreover, functional prediction revealed that the carnivores had a significantly higher percentage of base excision repair, glycerolipid metabolism, taurine and hypotaurine metabolism, inorganic ion transport and metabolism, and nucleotide metabolism; while arginine and proline metabolism showed enrichment in the herbivore group. Source-tracking analysis showed that the contributions of bacteria from maternal milk to the microbiota of neonates of different mammals were different at day 3 after neonatal birth. Overall, our findings provided a theoretical basis for the maternal milk microbiota to affect neonatal fecal microbiota at day 3 after neonatal birth.

The regimens containing levofloxacin (LVX) have been recommended as an alternate to standard triple therapy to treat Helicobacter pylori infections and H pylori mixed infection always lead to H pylori chronic infection. Although the molecular mechanism of LVX resistance with gyrA gene mutation has been clearly understood in H pylori , other genes involved in antibiotic resistance remain unclear. Efflux pump plays an important role in clinically relevant multidrug resistance. Furthermore, the relationship between the strains with different LVX level-resistances from individuals is also unknown. Helicobacter pylori monoclonal strains were isolated from patients with eradication failure. E test was used to detect the minimal inhibitory concentration of LVX. One lower-level LVX-resistant clone and 2 higher-level LVX-resistant clones from the same patient were selected to sequence the complete genomes. Single-nucleotide variants (SNVs) and mutations were extracted and analyzed from gryA and resistance-nodulation-division family efflux genes. Two clones with higher-level resistance had the mutation pattern of Asn87Lys and one lower-level LVX-resistant clone had an Asp91Asn mutation. Compared to clones with higher-level resistance, the higher genetic variations were found in genes belonging to the resistance-nodulation-division family in H pylori strains with lower-level resistance to LVX. There were significantly more SNVs of Hp0970 (hefE) and Hp1329 (hefI) in the lower-level LVX-resistant clone than those in the higher-level LVX-resistant clones ( P = .044). The mutation pattern of the Asn87Lys of the gyrA gene confers a higher resistance to LVX than that of the Asp91Asn in H pylori . Increase in the number of SNVs of the Hp0970 (hefE) and Hp1329 (hefI) genes change the resistance to LVX. Twelve mutations verified by Sanger sequencing in Hp0970 (hefE) and Hp1329 (hefI) may decrease resistant levels to LVX.

Objectives : To determine the risk factors associated with persistent airflow limitation in patients with asthma. Method s: This study was designed and carried out in the department of respiratory medicine, fourth People’s Hospital of Jinan City, Shandong province, China between Jan 2012 and Dec 2012. Three hundred and six asthma patients participating in the study were divided into persistent airflow limitation group (PAFL) and no persistent airflow limitation group (NPAFL). The patients participated in pulmonary function tests and sputum induction examination. The clinical data including age, gender, onset age, disease course, smoking history, family history, regular corticosteroid inhalation, hospitalization history and presence of atopy were collected. Results : In 306 patients, 128 (40.5%) were included in PAFL group and 178(59.5%) in NPAFL group. Multivariate analysis demonstrated smoking (≥10 pack-years; OR, 7.1; 95% CI, 1.8 to 31.2), longer asthma duration (≥ 20years) (OR, 6.3; 95% CI, 1.7 to 28.5), absence of regular corticosteroid inhalation (OR, 3.5; 95% CI, 1.1 to 14.5) and neutrophil in induced sputum≥65% (OR, 1.8; 95% CI, 1.0 to 2.8) were independent risk factors for PAFL. Conclusions : Smoking, longer asthma duration and increased neutrophil in induced sputum are risk factors for PAFL, while regular corticosteroid inhalation is protective factor. Smoking cessation and regular corticosteroid inhalation may play an important role in preventing the occurrence of persistent airflow limitation group (PAFL).