Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis.

INTRODUCTION Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. METHODS Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10-17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. RESULTS A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from 7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3 . Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3 . This decline was observed across all regions, in males and females. CONCLUSIONS Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood

Phagocytosis Escape by a Staphylococcus aureus Protein That Connects Complement and Coagulation Proteins at the Bacterial Surface

Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N-terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a ‘capsule’-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein

Dynamic handgrip exercise for the evaluation of mitral valve regurgitation: an echocardiographic study to identify exertion induced severe mitral regurgitation

Handgrip exercise (HG) has been occasionally used as a stress test in echocardiography. The effect of HG on mitral regurgitation (MR) is not well known. This study aims to evaluate this effect and the possible role of HG in the echocardiographic evaluation of MR. 722 patients with MR were included (18% primary, 82% secondary disease). We calculated effective regurgitant orifice area (EROA) and regurgitant volume (RVOL) at rest and during dynamic HG. Increase in MR was defined as any increase in EROA or RVOL. We analyzed the data to identify possible associations between clinical or echocardiographic parameters and the effect of HG on MR. MR increased during dynamic HG in 390 of 722 patients (54%) (∆EROA = 25%, ∆RVOL = 27%). Increase of regurgitation occurred in 66 of 132 patients with primary MR (50%) and in 324 of 580 patients with secondary MR (55%). This increase was associated with larger baseline EROA and RVOL, but it was independent from other clinical or echocardiographic parameters. In secondary MR, dynamic HG led to a reclassification of regurgitation severity from non-severe at rest to severe MR during HG in 104 of 375 patients (28%). There was a significant association between this upgrade in MR classification and higher New York Heart Association (NYHA) class (OR 1.486, 95%-CI 1.138-1.940, p = 0.004). Dynamic HG exercise increases MR in about half of patients independent of the etiology. Dynamic HG may be used to identify symptomatic patients with non-severe secondary MR at rest but severe MR during exercise