New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Cost-effectiveness of replacing versus discarding the nail in children with nail bed injury

Every year in the UK, around 10 000 children need to have operations to mend injuries to the bed of their fingernails. Currently, most children have their fingernail placed back on the injured nail bed after the operation. The NINJA trial found that children were slightly less likely to have an infection if the nail was thrown away rather than being put back, but the difference between groups was small and could have be due to chance. This study looked at whether replacing the nail is cost-effective compared with throwing it away. Using data from the NINJA trial, we compared costs, healthcare use, and quality of life and assessed the cost-effectiveness of replacing the nail. It was found that throwing the nail away after surgery would save the National Health Service (NHS) £75 (€85) per operation compared with placing the nail back on the nail bed. Changing clinical practice could save the NHS in England £720 000 (€819 000) per year

Effects of Summer Grazing Strategies on Organic Reserves and Root Characteristics of Big Bluestem

Quantifying root structure response to multiple defoliation events in a grazing situation is critical in developing management plans for warm-season tall grasses. A pasture experiment was conducted in 1999, 2000, and 2001 near Mead, NE. The objective of the experiment was to determine the effect of timing and frequency of grazing on big blue- stem (Andropogon gerardii Vitman) etiolated tiller growth and root and rhizome structure. Paddocks were grazed at a stocking rate of 9.9 Animal Unit Month (AUM) ha-1 in two to four cycles from mid-May to early-September. In April 2002, five 6.6- 132-cm soil cores were extracted from each paddock. Soil cores were subsampled at 30-cm depth increments for estimates of root mass, root surface area, and root volume. Etiolated tiller tents were used to estimate organic reserves of big bluestem in each paddock in spring 2002. Mean number and weight of etiolated tillers were reduced by up to 40% and 50%, respectively, in paddocks grazed in a sequence of June after internode elongation, early August, and early September. Root structure in the top 30 cm of the soil profile was affected most by multiple defoliation events with \u3c40 d of recovery between grazing periods. Root mass decreased by 25%, while mean surface area and volume of roots declined 10 and 15%, respectively, in the upper 30 cm of the soil profile in paddocks grazed in the sequence of post-internode elongation in June, early- August, and early-September. To maintain vigorous big blue-stem pastures, grazing management should concentrate on the elongation and post-elongation periods. Grazing at the elongation stage should be rotated among paddocks in successive years and the recovery period following grazing at internode elongation should be \u3e40 d

Phenotypic differences in viral immune escape explained by linking within-host dynamics to host-population immunity

Viruses that do not cause life-long immunity persist by evolving rapidly in response to prevailing host immunity. The immune-escape mutants emerge frequently, displacing or co-circulating with native strains even though mutations conferring immune evasion are often detrimental to viral replication. The epidemiological dynamics of immune-escape in acute-infection viruses with high transmissibility have been interpreted mainly through immunity dynamics at the host population level, despite the fact that immune-escape evolution involves dynamical processes that feedback across the within- and between-host scales. To address this gap, we use a nested model of within- and between-host infection dynamics to examine how the interaction of viral replication rate and cross-immunity imprint host population immunity, which in turn determines viral immune escape. Our explicit consideration of direct and immune-mediated competitive interactions between strains within-hosts revealed three insights pertaining to risk and control of viral immune-escape: (1) replication rate and immune-stimulation deficiencies (i.e., original antigenic sin) act synergistically to increase immune escape, (2) immune-escape mutants with replication deficiencies relative to their wildtype progenitor are most successful under moderate cross-immunity and frequent re-infections, and (3) the immunity profile along short host-transmission chains (local host-network structure) is a key determinant of immune escape

Incorporating different proportions of exotic maize germplasm into two adapted populations

Maize breeders frequently wish to use exotic germplasm in their breeding programs without losing specific characteristics of their adapted material. The objective of this study was to determine the optimal proportions of exotic germplasm to incorporate into adapted populations (F2 = 50% exotic, BC1 = 25% exotic, BC2 = 12.5% exotic and BC3 = 6.25% exotic) to form the initial foundation population and to determine the heterosis between adapted x exotics. We used six exotic populations of different origins and two adapted populations representing a Brazilian heterotic pattern. In 1993-94 and 1994-95, the parents, F1, F2, BC1, BC2, BC3 and four checks were evaluated in six environments in central Brazil using an 8 x 9 simple rectangular lattice design. Higher mean values for yield were obtained as the proportion of exotic germplasm decreased. Some backcrosses produced more than the adapted populations BR 105 (7.59 ton/ha) and BR 106 (8.43 ton/ha). The best results were obtained when incorporating 6.25 or 12.5% of exotic genes. This trend was true for root lodging, stalk lodging and ear diseases but not for plant and ear height. The midparent heterosis for yield varied from -16.1 to 40.3%. Midparent heterosis with positive and negative values were also found for the other traits. The results indicate the potential of exotic germplasm for developing good hybrids. After choosing the best exotic source, some recurrent selection might be appropriate in order to adapt and improve the exotic populations.<br>Os melhoristas de milho que utilizam germoplasmas exóticos nos programas de melhoramento têm a preocupação de não perder as características desejáveis dos materiais adaptados. Buscando atender esta demanda, o presente trabalho teve por objetivo determinar a proporção ideal de germoplasma exótico que deve ser incorporado em populações melhoradas (F2 = 50% exótico; RC1 = 25% exótico; RC2 = 12,5% exótico; RC3 = 6,25% exótico), para formar as populações base para seleção e determinar a heterose entre os germoplasmas exóticos e adaptados. Em 1993/94 e 1994/95, os parentais, F1, F2, RC1, RC2, RC3 e quatro testemunhas foram avaliados em seis ambientes da região central do Brasil, utilizando-se o delineamento em látice simples 8 x 9. De um modo geral, à medida que a proporção de germoplasma exótico decresceu, valores médios mais altos foram obtidos para o caráter peso de espigas. Alguns retrocruzamentos produziram mais que as populações melhoradas BR 105 (7.500 kg/ha) e BR 106 (8.430 kg/ha). Os melhores resultados foram obtidos quando houve a incorporação de 6,25 ou 12,5% de genes exóticos. Esta tendência foi observada para acamamento, quebramento e espigas doentes, mas não para altura de planta e de espiga. A heterose média para peso de espiga variou de -16,1 a 40,3%. Heteroses médias com valores positivos e negativos também foram encontradas para outros caracteres. Os resultados obtidos mostraram o potencial em se utilizar germoplasmas exóticos para a obtenção de híbridos. Sugere-se, após a escolha dos germoplasma, algum esquema de seleção recorrente para adaptar e melhorar as populações exóticas