Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials.

While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO. Analyses were adjusted for randomized treatment arm, age, sex, and ancestry. Results were pooled in a meta-analysis, and were evaluated for enrichment of MS risk variants. Variant colocalization and cell-specific expression analyses were performed using published cohorts. The strongest peaks were in PTPRD (rs77321193-C/A, p = 3.9 × 10-7) for BV change, and NEDD4L (rs11398377-GC/G, p = 9.3 × 10-8) for T2LV change. Evidence of colocalization was observed for NEDD4L, and both genes showed increased expression in neuronal and/or glial populations. No association between MS risk variants and MRI outcomes was observed. In this unique, precompetitive industry partnership, we report putative regions of interest in the neurodevelopmental gene PTPRD, and the ubiquitin ligase gene NEDD4L. These findings are distinct from known MS risk genetics, indicating an added role for genetic progression analyses and informing drug discovery.

The international serious adverse events consortium.

The International Serious Adverse Events Consortium is generating novel insights into the genetics and biology of drug-induced serious adverse events, and thereby improving pharmaceutical product development and decision-making.

Early warning indicators for first-line virologic failure independent of adherence measures in a South African urban clinic.

We sought to develop individual-level Early Warning Indicators (EWI) of virologic failure (VF) for clinicians to use during routine care complementing WHO population-level EWI. A case-control study was conducted at a Durban clinic. Patients after ≥ 5 months of first-line antiretroviral therapy (ART) were defined as cases if they had VF [HIV-1 viral load (VL)>1000 copies/mL] and controls (2:1) if they had VL ≤ 1000 copies/mL. Pharmacy refills and pill counts were used as adherence measures. Participants responded to a questionnaire including validated psychosocial and symptom scales. Data were also collected from the medical record. Multivariable logistic regression models of VF included factors associated with VF (p<0.05) in univariable analyses. We enrolled 158 cases and 300 controls. In the final multivariable model, male gender, not having an active religious faith, practicing unsafe sex, having a family member with HIV, not being pleased with the clinic experience, symptoms of depression, fatigue, or rash, low CD4 counts, family recommending HIV care, and using a TV/radio as ART reminders (compared to mobile phones) were associated with VF independent of adherence measures. In this setting, we identified several key individual-level EWI associated with VF including novel psychosocial factors independent of adherence measures.

Assessment of fungal isolates for development of a myco-acaricide for cattle tick control.

Entomopathogenic fungal isolates of Arachnid origin were assessed for their ability to produce mortality and inhibit egg hatching in Boophilus microplus with the aim of selecting an isolate for development into a myco-acaricide for control of cattle ticks. The ability of the most promising isolate to target developmental stages of more than one tick species and the optimum concentration of fungal inoculum to be used for future studies were determined. Metarhizium anisopliae was the most pathogenic of the three fungal species tested on B. microplus, producing shorter average survival times (ASTs) for engorged adults (AST = 5.2 +/- 0.1 days) and larvae (AST = 9.3 +/- 0.4 days), and a longer average hatching times (AHT; AHT = 19.8 +/- 0.5 days) in comparison to Simplicillium lamellicola and Paecilomyces farinosus. In comparative studies on two tick species with similar life cycles, M. anisopliae produced a shorter AST in engorged adult B. microplus (AST = 8.8 +/- 0.3 days) than Rhipicephalus sanguineus (AST = 10.3 +/- 0.3 days). M. anisopliae was pathogenic to larvae of B. microplus (AST = 7.7 +/- 0.4 days), however, had no effect on larvae of R. sanguineus (AST = 14.6 +/- 0.3 days) as the AST of this treatment was similar to its untreated control (AST = 14.1 +/- 0.4 days). M. anisopliae lengthened the AHTs in both B. microplus (AHT = 16.4 +/- 0.3 days) and R. sanguineus (AHT = 16.7 +/- 0.3 days) in comparison to the controls. The ASTs of engorged adult B. microplus treated with M. anisopliae shortened as the concentration was increased from 1 x 10(7) to 5 x 10(8) conidia/ mL. A further increase in concentration, 1 x 10(9) conidia/mL (AST = 10.2 +/- 0.4 days) did not shorten or lengthen the AST in comparison to 5 x 10(8) conidia/mL (AST = 9.4 +/- 0.3 days).