on behalf of the HAWK and HARRIER Study Investigators* Purpose: Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a singlechain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD).Design: Double-masked, multicenter, active-controlled, randomized trials. Participants: Patients (N ¼ 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.Intervention: Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing.Main Outcome Measures: The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes.Results: At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, þ6.6 [6 mg] and þ6.1 [3 mg] letters with brolucizumab vs. þ6.8 letters with aflibercept [HAWK]; þ6.9 [brolucizumab 6 mg] vs. þ7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mgetreated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mgetreated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P ¼ 0.001) and HARRIER (22.7% vs. 32.2%; P ¼ 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean À172.8 mm vs. À143.7 mm; P ¼ 0.001) and HARRIER (LS mean À193.8 mm vs. À143.9 mm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept.Conclusions: Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mgetreated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (Clin-icalTrials.gov; NCT02307682, NCT02434328).
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Stressful situations reduce the welfare, production indices and immune status of chickens. Salmonella spp. are a major zoonotic pathogens that annually cause over 1 billion infections worldwide. We therefore designed the current experiment to analyse the effects of 31±1°C heat stress (HS) (from 35 to 41 days) on performance parameters, Salmonella invasion and small intestine integrity in broiler chickens infected with Salmonella Enteritidis. We observed that HS decreased body weight gain and feed intake. However, feed conversion was only increased when HS was combined with Salmonella Enteritidis infection. In addition, we observed an increase in serum corticosterone levels in all of the birds that were subjected to HS, showing a hypothalamus-pituitary-adrenal axis activation. Furthermore, mild acute multifocal lymphoplasmacytic enteritis, characterized by foci of heterophil infiltration in the duodenum, jejunum and ileum, was observed in the HS group. In contrast, similar but more evident enteritis was noted in the heat-stressed and Salmonella-infected group. In this group, moderate enteritis was observed in all parts of the small intestine. Lastly, we observed an increase in Salmonella counts in the spleens of the stressed and Salmonella-infected chickens. The combination of HS and Salmonella Enteritidis infection may therefore disrupt the intestinal barrier, which would allow pathogenic bacteria to migrate through the intestinal mucosa to the spleen and generate an inflammatory infiltrate in the gut, decreasing performance parameters.
Overcrowding stress is a reality in the poultry industry. Chickens exposed to long-term stressful situations present a reduction of welfare and immunosuppression. We designed this experiment to analyse the effects from overcrowding stress of 16 birds/m 2 on performance parameters, serum corticosterone levels, the relative weight of the bursa of Fabricius, plasma IgA and IgG levels, intestinal integrity, macrophage activity and experimental Salmonella Enteritidis invasion. The results of this study indicate that overcrowding stress decreased performance parameters, induced enteritis and decreased macrophage activity and the relative bursa weight in broiler chickens. When the chickens were similarly stressed and infected with Salmonella Enteritidis, there was an increase in feed conversion and a decrease in plasma IgG levels in the stressed and Salmonella-infected birds. We observed moderate enteritis throughout the duodenum of chickens stressed and infected with Salmonella. The overcrowding stress decreased the macrophage phagocytosis intensity and increased Salmonella Enteritidis counts in the livers of birds challenged with the pathogenic bacterium. Overcrowding stress via the hypothalamic-pituitary-adrenal axis that is associated with an increase in corticosterone and enteritis might influence the quality of the intestinal immune barrier and the integrity of the small intestine. This effect allowed pathogenic bacteria to migrate through the intestinal mucosa, resulting in inflammatory infiltration and decreased nutrient absorption. The data strengthen the hypothesis that control of the welfare of chickens and avoidance of stress from overcrowding in poultry production are relevant factors for the maintenance of intestinal integrity, performance and decreased susceptibility to Salmonella infection.
The rare form of retinal dystrophy, Bietti crystalline dystrophy, is associated with variations in CYP4V2, a member of the cytochrome P450 family. This study reports patients affected by typical and atypical Bietti crystalline dystrophy, expanding the spectrum of this disease. This is an observational case series of patients with a clinical and molecular diagnosis of Bietti crystalline dystrophy that underwent multimodal imaging. Four unrelated patients are described with two known variants, c.802-8_810del17insGC and c.518T > G (p.Leu173Trp), and one novel missense variant, c.1169G > T (p.Arg390Leu). The patient with the novel homozygous variant had the most severe phenotype resulting in macular hole formation and retinal detachment in both eyes. To the best of our knowledge, there is no association of these features with Bietti crystalline dystrophy. Patient 1 was the youngest patient and had the mildest phenotype with crystals in the retina without chorioretinal atrophy and visual complaints. Patients 2 and 3 presented with fewer crystals and chorioretinal atrophy. These three patients presented a classic phenotype. The fourth patient presented with an atypical and severe phenotype. This study reveals a new genotype and new phenotype associated with this disorder.
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