Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Slow Walking in Individuals with Chronic Post-Stroke Hemiparesis: Speed Mediated Effects of Gait Kinetics and Ankle Kinematics.

Post-stroke rehabilitation often aims to increase walking speeds, as faster walking is associated with improved functional status and quality of life. However, for successful community ambulation, ability to modulate (increase and decrease) walking speeds is more important than walking continuously at constant speeds. Increasing paretic propulsive forces to increase walking speed has been extensively examined; however, little is known about the mechanics of slow walking post-stroke. The primary purpose of this study was to identify the effects of increased and decreased walking speeds on post-stroke kinetics and ankle kinematics. Fifteen individuals with chronic post-stroke hemiparesis and 15 non-neurologically impaired controls walked over an instrumented treadmill under: slow, self-selected, and fast walking speeds. We examined the peak propulsive forces, propulsive impulse, peak braking forces, braking impulse, and ankle kinematics under each condition. When walking at slow walking speeds, paretic limbs were unable to reduce braking impulse and peak propulsive force or modulate ankle kinematics. Impaired modulation of paretic gait kinetics during slow walking places people post-stroke at high risks for slip-related falls. These findings suggest the need for developing gait retraining paradigms for slow walking in individuals chronically post-stroke that target the ability of the paretic limb to modulate braking forces.

Ambient alkaline hydrolysis and anaerobic digestion as a mortality management strategy for whole poultry carcasses.

Livestock mortality management is a critical factor for ensuring biosecurity, minimizing environmental impact, and maintaining public trust in livestock production agriculture. The number of technologies currently used for livestock mortality management is small, including composting, burial, incineration, landfilling, and rendering. Each technology has advantages and disadvantages which make their suitability situational. In this study, ambient alkaline hydrolysis (AAH) using 2, 4, or 8 M potassium hydroxide at ambient temperature and pressure was explored as a disposal method for whole broiler chicken carcasses. Alkaline hydrolysate (pH > 14) resulting from the process was neutralized by mixing with acidic corn silage, and then utilized as a substrate for anaerobic digestion in bench top continuously stirred tank reactors. All AAH treatments solubilized broiler carcasses within 20 days. Corn silage neutralized 2 M hydrolysate using a 2:1 (w/w) mixing ratio, while 4 M hydrolysate required a 4:1 mixing ratio. Anaerobic digestion of neutralized hydrolysate reduced volatile solids by >96% for all treatments. Highest methane yields were observed from the 2 M hydrolysate (607.2 ±â€¯47.9 g mL-1 VS), while biogas production from the 8 M hydrolysate was totally inhibited over a total of 42 days. Ambient alkaline hydrolysis followed by silage neutralization and anaerobic digestion provides a feasible, straightforward technology to manage routine and emergency animal mortalities.

High concentration biotherapeutic formulation and ultrafiltration: Part 1 pressure limits.

High therapeutic dosage requirements and the desire for ease of administration drive the trend to subcutaneous administration using delivery systems such as subcutaneous pumps and prefilled syringes. Because of dosage volume limits, prefilled syringe administration requires higher concentration liquid formulations, limited to about 30 cP or roughly 100-300 g L-1 for mAb's. Ultrafiltration (UF) processes are routinely used to formulate biological therapeutics. This article considers pressure constraints on the UF process that may limit its ability to achieve high final product concentrations. A system hardware analysis shows that the ultrafiltration cassette pressure drop is the major factor limiting UF systems. Additional system design recommendations are also provided. The design and performance of a new cassette with a lower feed channel flow resistance is described along with 3D modeling of feed channel pressure drop. The implications of variations in cassette flow channel resistance for scaling up and setting specifications are considered. A recommendation for a maximum pressure specification is provided. A review of viscosity data and theory shows that molecular engineering, temperature, and the use of viscosity modifying excipients including pH adjustment can be used to achieve higher concentrations. The combined use of a low pressure drop cassette with excipients further increased final concentrations by 35%. Guidance is provided on system operation to control hydraulics during final concentration. These recommendations should allow one to design and operate systems to routinely achieve the 30 cP target final viscosity capable of delivery using a pre-filled syringe. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:113-124, 2017.