ConclusionsS-OIV infection can cause severe illness, the acute respiratory distress syndrome, and death in previously healthy persons who are young to middle-aged. None of the secondary infections among health care workers were severe.

No abstract

The IL-17 pathway is an established driver of psoriasis pathogenesis. We examined the detailed molecular and cellular effects of blockade of IL-17 signaling in human psoriatic skin before and following treatment with brodalumab, a competitive inhibitor of the IL-17 Receptor A subunit. Thousands of aberrantly expressed genes in lesional skin normalized within 2 weeks following brodalumab treatment, with conversion of the lesional psoriasis transcriptome to resemble that seen in nonlesional skin. Keratinocyte-expressed genes appeared to normalize rapidly, whereas T cell–specific normalization occurred over six weeks. The three IL-17 ligand genes that are upregulated in lesional skin, IL17A, IL17C, and IL17F, were all downregulated in a dose-dependent manner following brodalumab treatment. Cellular measures also showed a similar pattern with dramatic decreases in keratinocyte hyperplasia within one week, and decreases in infiltrating leukocytes occurred over a longer timescale. Individuals with the highest brodalumab exposure showed normalization of both IL-17–responsive genes and the psoriasis transcriptome, whereas subjects with lower exposures showed transient or incomplete molecular responses. Clinical and molecular response appeared dependent on the extent of brodalumab exposure relative to the expression of IL-17 ligand genes, and reduction of IL-17 signaling into the nonlesional range was strongly correlated with normalization of the psoriasis transcriptome. These data indicate that blockade of IL-17 signaling in psoriatic skin leads to rapid transcriptomal changes initially in keratinocyte-expressed genes, followed by normalization in the leukocyte abnormalities, and demonstrates the essential role of the IL-17R on keratinocytes in driving disease pathogenesis.

This prospective and controlled pilot study evaluates the long-term effects of nocturnal oxygen therapy (NOT) on exercise endurance, hematology variables, quality of life, and survival of 23 adult patients (mean age, 32 +/- 6 yr) with post-tricuspid congenital heart defects (ventricular septal defect = 10; patent ductus arteriosus = 13) and Eisenmenger Syndrome. All had pulmonary hypertension (mean pulmonary artery pressure = 88 +/- 20 mm Hg), severe hypoxemia (Pa(O(2)) = 44 +/- 5 mm Hg), and secondary erythrocytosis (hematocrit = 61.5 +/- 7%). Exercise endurance (6-min walk test = 380 +/- 88 m) was limited. In a random fashion, NOT was given to one group of patients (n = 12) but withheld from a comparable control group (n = 11). At 2 yr of close follow-up, two patients in the group of control patients, and three in the treatment group died. Mean survival estimates were similar in both groups (20.7 versus 20.8 mo; chi-square log-rank, 0.08; p = NS). Likewise, none of the hematology, exercise capacity, and quality of life variables examined showed statistically significant changes that were dependent on treatment regimen. We conclude that NOT does not modify the natural history of patients with advanced Eisenmenger Syndrome.

Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin-induced dermal blood flow, with no apparent dose-dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention.