Screening for Elder Abuse in the Veterans Health Administration: Varied Approaches Across a National Health System.

BACKGROUND: Elder abuse (EA) is common and has devastating health consequences yet is rarely detected by healthcare professionals. While EA screening tools exist, little is known about if and how these tools are implemented in real-world clinical settings. The Veterans Health Administration (VHA) has experience screening for, and resources to respond to, other forms of interpersonal violence and may provide valuable insights into approaches for EA screening. OBJECTIVE: Describe EA screening practices across a national integrated healthcare system serving a large population of older adults at risk for EA. DESIGN: Survey of all 139 VHA medical centers from January to August 2021. PARTICIPANTS: Surveys were completed by the Social Work Chief, or delegate, at each site. MAIN MEASURES: The survey assessed the presence and characteristics of EA-specific screening practices as well as general abuse/neglect screening conducted with patients of all ages, including older adults. Follow-up emails were sent to sites that reported screening requesting additional details not included in the initial survey. KEY RESULTS: Overall, 130 sites (94%) responded. Among respondents, 5 (4%) reported screening older adults for EA using a previously published tool, while 6 (5%) reported screening for EA with an unstudied or locally developed tool. Forty-eight percent reported screening patients of all ages for general abuse/neglect using unstudied questions/tools, and 44% reported no EA screening at their site. Characteristics of screening programs (e.g., frequency, clinical setting, provider type) varied widely between sites, as did respondents' understanding of the definition of screening. CONCLUSIONS: High variability in screening practices for abuse/neglect and lack of EA-specific screening in a system that has successfully deployed other standardized screening approaches present an important opportunity to standardize and improve EA detection practices. Lessons learned in VHA could help advance the evidence base for EA screening more broadly to increase overall detection rates for EA nationally.

The AibR-isovaleryl coenzyme A regulator and its DNA binding site - a model for the regulation of alternative de novo isovaleryl coenzyme A biosynthesis in Myxococcus xanthus.

Isovaleryl coenzyme A (IV-CoA) is an important building block of iso-fatty acids. In myxobacteria, IV-CoA is essential for the formation of signaling molecules involved in fruiting body formation. Leucine degradation is the common source of IV-CoA, but a second, de novo biosynthetic route to IV-CoA termed AIB (alternative IV-CoA biosynthesis) was recently discovered in M. xanthus. The AIB-operon contains the TetR-like transcriptional regulator AibR, which we characterize in this study. We demonstrate that IV-CoA binds AibR with micromolar affinity and show by gelshift experiments that AibR interacts with the promoter region of the AIB-operon once IV-CoA is present. We identify an 18-bp near-perfect palindromic repeat as containing the AibR operator and provide evidence that AibR also controls an additional genomic locus coding for a putative acetyl-CoA acetyltransferase. To elucidate atomic details, we determined crystal structures of AibR in the apo, the IV-CoA- and the IV-CoA-DNA-bound state to 1.7 Å, 2.35 Å and 2.92 Å, respectively. IV-CoA induces partial unfolding of an α-helix, which allows sequence-specific interactions between AibR and its operator. This study provides insights into AibR-mediated regulation and shows that AibR functions in an unusual TetR-like manner by blocking transcription not in the ligand-free but in the effector-bound state.

Aminolaevulinic acid synthase of Rhodobacter capsulatus: high-resolution kinetic investigation of the structural basis for substrate binding and catalysis.

The first enzyme of haem biosynthesis, ALAS (5-aminolaevulinic acid synthase), catalyses the pyridoxal 5'-phosphate-dependent condensation of glycine and succinyl-CoA to 5-aminolaevulinic acid, CO(2) and CoA. The crystal structure of Rhodobacter capsulatus ALAS provides the first snapshots of the structural basis for substrate binding and catalysis. To elucidate the functional role of single amino acid residues in the active site for substrate discrimination, substrate positioning, catalysis and structural protein rearrangements, multiple ALAS variants were generated. The quinonoid intermediates I and II were visualized in single turnover experiments, indicating the presence of an α-amino-ß-oxoadipate intermediate. Further evidence was obtained by the pH-dependent formation of quinonoid II from the product 5-aminolaevulinic acid. The function of Arg(21), Thr(83), Asn(85) and Ile(86), all involved in the co-ordination of the succinyl-CoA substrate carboxy group, were analysed kinetically. Arg(21), Thr(83)and Ile(86), all of which are located in the second subunit to the intersubunit active site, were found to be essential. Their location in the second subunit provides the basis for the required structural dynamics during the complex condensation of both substrates. Utilization of L-alanine by the ALAS variant T83S indicated the importance of this residue for the selectiveness of binding with the glycine substrate compared with related amino acids. Asn(85) was found to be solely important for succinyl-CoA substrate recognition and selectiveness of binding. The results of the present study provide a novel dynamic view on the structural basis of ALAS substrate-binding and catalysis.

Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus.

Gliotoxin is an epipolythiodioxopiperazine (ETP) class toxin, contains a disulfide bridge that mediates its toxic effects via redox cycling and is produced by the opportunistic fungal pathogen Aspergillus fumigatus Self-resistance against gliotoxin is effected by the gliotoxin oxidase GliT, and attenuation of gliotoxin biosynthesis is catalysed by gliotoxin S-methyltransferase GtmA. Here we describe the X-ray crystal structures of GtmA-apo (1.66 Å), GtmA complexed to S-adenosylhomocysteine (1.33 Å) and GtmA complexed to S-adenosylmethionine (2.28 Å), providing mechanistic insights into this important biotransformation. We further reveal that simultaneous elimination of the ability of A. fumigatus to dissipate highly reactive dithiol gliotoxin, via deletion of GliT and GtmA, results in the most significant hypersensitivity to exogenous gliotoxin observed to date. Indeed, quantitative proteomic analysis of ΔgliT::ΔgtmA reveals an uncontrolled over-activation of the gli-cluster upon gliotoxin exposure. The data presented herein reveal, for the first time, the extreme risk associated with intracellular dithiol gliotoxin biosynthesis-in the absence of an efficient dismutation capacity. Significantly, a previously concealed protective role for GtmA and functionality of ETP bis-thiomethylation as an ancestral protection strategy against dithiol compounds is now evident.