Antidementia Medication Use in Nursing Home Residents.

BACKGROUND: Antidementia medication can provide symptomatic improvements in patients with Alzheimer's disease, but there is a lack of consensus guidance on when to start and stop treatment in the nursing home setting. METHODS: We describe utilization patterns of cholinesterase inhibitors (ChEI) and memantine for 3,50,197 newly admitted NH residents with dementia between 2011 and 2018. RESULTS: Overall, pre-admission use of antidementia medications declined from 2011 to 2018 (ChEIs: 44.5% to 36.9%; memantine: 27.4% to 23.2%). Older age, use of a feeding tube, and greater functional dependency were associated with lower odds of ChEI initiation. Coronary artery disease, parenteral nutrition, severe aggressive behaviors, severe cognitive impairment, and high functional dependency were associated with discontinuation of ChEIs. Comparison of clinical factors related to anti-dementia drug treatment changes from pre to post NH admission in 2011 and 2018 revealed a change toward lower likelihood of initiation of treatment among residents with more functional dependency and those with indicators of more complex illness as well as a change toward higher likelihood of discontinuation in residents having 2 or more hospital stays. CONCLUSIONS: These prescribing trends highlight the need for additional research on the effects of initiating and discontinuing antidementia medications in the NH to provide clear guidance for clinicians when making treatment decisions for individual residents.

Epidemiological and clinical features of Panton-Valentine Leukocidin positive Staphylococcus aureus bacteremia: A case-control study.

BACKGROUND: Panton-Valentine Leukocidin (PVL) toxin in Staphylococcus aureus has been associated with both severe pneumonia and skin and soft tissue infections. However, there are only limited data on how this virulence factor may influence the clinical course or complications of bacteremic S. aureus infections. METHODS: Between September 2016 and March 2018, S. aureus isolates from clinical cultures from hospitals in an academic medical center underwent comprehensive genomic sequencing. Four hundred sixty-nine (29%) of 1681 S. aureus sequenced isolates were identified as containing the genes that encode for PVL. Case patients with one or more positive blood cultures for PVL were randomly matched with control patients having positive blood cultures with lukF/lukS-PV negative (PVL strains from a retrospective chart review). RESULTS: 51 case and 56 control patients were analyzed. Case patients were more likely to have a history of injection drug use, while controls more likely to undergo hemodialysis. Isolates from 78.4% of case patients were methicillin resistant as compared to 28.6% from control patients. Case patients had a higher incidence of pneumonia and skin and soft tissue infection and longer duration of fever without differences in length of bacteremia. Clinical cure or expiration was comparable. CONCLUSIONS: These results are consistent with prior observations associating the PVL toxin with both community-acquired MRSA strains as well as severe staphylococcal pneumonia. The presence of the PVL toxin does not appear to otherwise influence the natural history of bacteremic S. aureus disease other than in prolonging the duration of fever.

Comprehensive fitness maps of Hsp90 show widespread environmental dependence.

Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard conditions and under five stress conditions. To our knowledge, these are the largest determined comprehensive fitness maps of point mutants. The growth of many variants differed between conditions, indicating that environment can have a large impact on Hsp90 evolution. Multiple variants provided growth advantages under individual conditions; however, these variants tended to exhibit growth defects in other environments. The diversity of Hsp90 sequences observed in extant eukaryotes preferentially contains variants that supported robust growth under all tested conditions. Rather than favoring substitutions in individual conditions, the long-term selective pressure on Hsp90 may have been that of fluctuating environments, leading to robustness under a variety of conditions.

Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution.

The evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on protein sequence evolution is interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. We compared our experimental results to the frequency of protease variants in a publicly available data set of 32,163 sequenced isolates from drug-naïve individuals. The most common amino acids in sequenced isolates supported robust experimental fitness, indicating that the experimental fitness landscape captured key features of selection acting on protease during viral infections of hosts. Amino acid changes requiring multiple mutations from the likely ancestor were slightly less likely to support robust experimental fitness than single mutations, consistent with the genetic code favoring chemically conservative amino acid changes. Amino acids that were common in sequenced isolates were predominantly accessible by single mutations from the likely protease ancestor. Multiple mutations commonly observed in isolates were accessible by mutational walks with highly fit single mutation intermediates. Our results indicate that the prevalence of multiple-base mutations in HIV-1 protease is strongly influenced by mutational sampling.