DESIGN: Double-masked, 100-week, multicenter, active-controlled, randomized trials.
METHODS: Subjects were randomized 1:1:1 to brolucizumab 3mg/6mg or aflibercept 2mg in KESTREL (N=566) or 1:1 to brolucizumab 6mg or aflibercept 2mg in KITE (N=360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with optional adjustment to q8w if disease activity was identified at pre-defined assessment visits; aflibercept groups received 5xq4w followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in DRSS score and anatomical and safety outcomes.
RESULTS: At Week 52, brolucizumab 6mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters versus +10.5 letters; KITE: +10.6 letters versus +9.4 letters; p<0.001), more subjects achieved central subfield thickness (CSFT) <280µm and fewer had persisting subretinal and/or intraretinal fluid versus aflibercept, with >50% of brolucizumab 6mg subjects maintained on q12w dosing after loading. In KITE, brolucizumab 6mg showed superior improvements in change of CSFT from baseline over Week 40-Week 52 versus aflibercept (p=0.001). The incidence of ocular serious adverse events was 3.7% (brolucizumab 3mg), 1.1% (brolucizumab 6mg), 2.1% (aflibercept) in KESTREL; 2.2% (brolucizumab 6mg), 1.7% (aflibercept) in KITE.
CONCLUSION: Brolucizumab 6mg showed robust visual gains and anatomical improvements with an overall favorable benefit/risk profile in patients with DME.
METHODS: Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS).
RESULTS: We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51-1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792).
CONCLUSIONS: The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial.
TRIAL REGISTRATION: The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.
RESULTS: We used 43,310 SNPs to infer the population structure, evidence of local adaptation and sources of introduction. The overall genetic differentiation of this species was low. The native populations were differentiated into three genetic clusters, corresponding to the Yangtze, Pearl and Heilongjiang River Systems, respectively. The populations in Malaysia, India and Nepal were introduced from both the Yangtze and Pearl River Systems. Loci and genes involved in putative local selection for native locations were identified. Evidence of both positive and balancing selection was found in the introduced locations. Genes associated with loci under putative selection were involved in many biological functions. Outlier loci were grouped into clusters as genomic islands within some specific genomic regions, which likely agrees with the divergence hitchhiking scenario of divergence-with-gene-flow.
CONCLUSIONS: This study, for the first time, sheds novel insights on the population differentiation of the grass carp, genetics of its strong ability in adaption to diverse environments and sources of some introduced grass carp populations. Our data also suggests that the natural populations of the grass carp have been affected by the aquaculture besides neutral and adaptive forces.
METHODS: Multistage sampling was used to recruit registered nurses from Hunan province in China. Registered nurses who identified themselves as experiencing adverse events from nine tertiary hospitals were included in this study. Participants were recruited to complete a survey on the second victim experience and support tool, the simplified coping style questionnaire, and the professional quality of life scale. The stress coping theory was used to develop the framework in this study. The structural equation modelling approach was used for conducting the mediating effects analysis via IBM SPSS Statistics 26.0 and Mplus 8.3.
RESULTS: In total, 67% (n = 899) of nurses reported a second victim experience during their careers. In a bivariate analysis, both second-victims experiences and coping styles were significantly associated with their professional quality of life. The results showed that the effects of second victim experiences on their professional quality of life were fully mediated by coping styles. A total of 10 significantly indirect pathways were estimated, ranging from -0.243 to 0.173.
CONCLUSIONS: Second-victim experiences are common among nurses in this study. Since the mediating effects of coping styles were clarified in this study, it is imperative to promote the perception of negative coping styles and encourage nurses to adopt more positive coping styles with adequate support systems.