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

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Issues involved with thermoactive geotechnical systems: characterization of thermomechanical soil behavior and soil-structure interface behaviour

This paper focuses on the main issues discussed during a session on the impact of thermohydromechanical behavior of soils on thermoactive geotechnical systems, and how they could affect the performance of thermoactive geotechnical systems. Both soil behavior as well as soil–structure interaction behavior was discussed. The main observation from the session was that the thermohydromechanical behavior of saturated soils has reached a mature understanding, with several established constitutive models that can be used by engineers. However, there are still opportunities to enhance these constitutive models by considering issues such as unsaturated conditions, anisotropic stress states, cyclic heating and cooling effects, and changes in the preconsolidation stress during heating and cooling. Further there are still opportunities to improve our understanding of soil/concrete interface behavior, including the development of novel testing approaches

Environmental impact calculations, life cycle cost analysis

This session explored the evaluation and characterization of the sustainability of thermoactive geotechnical systems. Thermoactive geotechnical systems take advantage of shallow geothermal energy by using the foundation of a structure as a heat source and sink for use with a ground source heat pump. Methods for their evaluation within a sustainability framework still need to be developed. This can be done within larger regulatory frameworks such as the Code for Sustainable Homes. The Life Cycle Analysis methodology has been used to examine non-thermoactive geotechnical systems using both embodied carbon and embodied energy as metrics. Life Cycle Analyses have also been performed on ground source heat pumps and can provide valuable insight into the indirect operational environmental impacts of thermoactive geotechnical systems

Building codes, green certification and implementation issues, market challenges

The purpose of this paper is to provide a current state of affairs regarding the existing building codes in relation to thermoactive foundations, if any exist at all. This paper also explores regional incentives in the form of energy and carbon requirements for new structures as a potential driver for thermoactive foundation implementation. Two Green Certification programs, LEED and BREEAM, are discussed which both offer credit for shallow geothermal energy systems. The actual implementation of thermoactive foundation technology has proved to be challenging due to the complications arising out of the concept development stage and the coordination required among the various parties involved in the design stage. A discussion of these challenges and an outline of the deliverables needed of those in academia and industry in order to progress is included

Phylogenomic Placement of American Southwest-Associated Clinical and Veterinary Isolates Expands Evidence for Distinct Cryptococcus gattii VGVI

Whole-genome sequencing has advanced our understanding of the population structure of the pathogenic species complex Cryptococcus gattii, which has allowed for the phylogenomic specification of previously described major molecular type groupings and novel lineages. Recently, isolates collected in Mexico in the 1960s were determined to be genetically distant from other known molecular types and were classified as VGVI. We sequenced four clinical isolates and one veterinary isolate collected in the southwestern United States and Argentina from 2012 to 2021. Phylogenomic analysis groups these genomes with those of the Mexican VGVI isolates, expanding VGVI into a clade and establishing this molecular type as a clinically important population. These findings also potentially expand the known Cryptococcus ecological range with a previously unrecognized endemic area. © 2022 by the authors.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]