Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Here we estimated the global prevalence and absolute burden of CKD in 2010 by pooling data from population-based studies. We searched MEDLINE (January 1990 to December 2014), International Society of Nephrology Global Outreach Program funded projects, and bibliographies of retrieved articles and selected 33 studies reporting gender- and age-specific prevalence of CKD in representative population samples. The age standardized global prevalence of CKD stages 1–5 in adults aged 20 and older was 10.4% in men (95% confidence interval 9.3–11.9%) and 11.8% in women (11.2–12.6%). This consisted of 8.6% men (7.3–9.8%) and 9.6% women (7.7–11.1%) in high-income countries, and 10.6% men (9.4–13.1%) and 12.5% women (11.8–14.0%) in low- and middle-income countries. The total number of adults with CKD was 225.7 million (205.7–257.4 million) men and 271.8 million (258.0–293.7 million) women. This consisted of 48.3 million (42.3–53.3 million) men and 61.7 million (50.4–69.9 million) women in high-income countries, and 177.4 million (159.2–215.9 million) men and 210.1 million (200.8–231.7 million) women in low- and middle-income countries. Thus, CKD is an important global-health challenge, especially in low- and middle-income countries. National and international efforts for prevention, detection, and treatment of CKD are needed to reduce its morbidity and mortality worldwide.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knock-down experiments (ABCA1, TRIB1) and clinical trial results (CCR2, CCR5), with consistent regulation. Finally we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including (gene symbols) EGF, IL16, PAPPA, SPON1, F3, ADM, CASP8, CHI3L1, CXCL16, GDF15, and MMP12. Taken together these findings demonstrate the utility of largescale mapping the genetics of the proteome, and provide a resource for future precision studies of circulating proteins in human health.

We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (N=886; NCT02684006), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib vs sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker PD-L1 nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR SNPs was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including novel immunomodulatory and angiogenesis gene expression signatures (GES), previously undescribed mutational profiles and their corresponding GES, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC.

A set of 1638 informative SNP markers easily assayed by the Amplifluor genotyping system were tested in 102 mouse strains, including the majority of the common and wild-derived inbred strains available from The Jackson Laboratory. Selected from publicly available databases, the markers are on average ∼1.5 Mb apart and, whenever possible, represent the rare allele in at least two strains. Amplifluor assays were developed for each marker and performed on two independent DNA samples from each strain. The mean number of polymorphisms between strains was 608±136 SD. Several tests indicate that the markers provide an effective system for performing genome scans and quantitative trait loci analyses in all but the most closely related strains. Additionally, the markers revealed several subtle differences between closely related mouse strains, including the groups of several 129, BALB, C3H, C57, and DBA strains, and a group of wild-derived inbred strains representing several Mus musculus subspecies. Applying a neighbor-joining method to the data, we constructed a mouse strain family tree, which in most cases confirmed existing genealogies.

IMPORTANCE Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis. OBJECTIVE To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis. DESIGN, SETTING, AND PARTICIPANTS A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site. INTERVENTIONS Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients achieving an Investigator's Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12. RESULTS Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%; P < .001, 2-sided), 16 of 54 patients receiving 100 mg of abrocitinib (29.6%; P < .001), and 3 of 52 patients receiving placebo (5.8%) achieved grades of clear or almost clear on the Investigator's Global Assessment scale with improvement of 2 grades or more; these rates correspond to maximum effect model-based estimates of 44.5% (95% CI, 26.7%-62.3%) for those receiving 200 mg of abrocitinib, 27.8% (95% CI, 14.8%-40.9%) for those receiving 100 mg of abrocitinib, and 6.3% (95% CI, −0.2% to 12.9%) for those receiving placebo. Reductions in the Eczema Area and Severity Index were 82.6% (90% CI, 72.4%-92.8%; P < .001) for those receiving 200 mg of abrocitinib, 59.0% (90% CI, 48.8%-69.3%; P = .009) for those receiving 100 mg of abrocitinib, and 35.2% (90% CI, 24.4%-46.1%) for those receiving placebo. Adverse events were observed in 184 of 267 patients (68.9%); the most frequently reported adverse events (in Ն3 patients in any group) were dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea. Dose-dependent decreases in platelet count were observed but trended upward toward baseline levels after week 4. CONCLUSIONS AND RELEVANCE Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic de...