Perioperative Opioid Prescribing Patterns and Readmissions After Total Knee Arthroplasty in a National Cohort of Veterans Health Administration Patients.

OBJECTIVE: Among Veterans Health Administration (VHA) patients who undergo total knee arthroplasty (TKA) nationally, what are the underlying readmission rates and associations with perioperative opioid use, and are there associations with other factors such as preoperative health care utilization? METHODS: We retrospectively examined the records of 5,514 TKA patients (primary N = 4,955, 89.9%; revision N = 559, 10.1%) over one fiscal year (October 1, 2010-September 30, 2011) across VHA hospitals nationwide. Opioid use was classified into no opioids, tramadol only, short-acting only, or any long-acting. We measured readmission within 30 days and the number of days to readmission within 30 days. Extended Cox regression models were developed. RESULTS: The overall 30-day hospital readmission rate was 9.6% (N = 531; primary 9.5%, revision 11.1%). Both readmitted patients and the overall sample were similar on types of preoperative opioid use. Relative to patients without opioids, patients in the short-acting opioids only tier had the highest risk for 30-day hospital readmission (hazard ratio = 1.38, 95% confidence interval = 1.14-1.67). Preoperative opioid status was not associated with 30-day readmission. Other risk factors for 30-day readmission included older age (≥66 years), higher comorbidity and diagnosis-related group weights, greater preoperative health care utilization, an urban location, and use of preoperative anticonvulsants. CONCLUSIONS: Given the current opioid epidemic, the routine prescribing of short-acting opioids after surgery should be carefully considered to avoid increasing risks of 30-day hospital readmissions and other negative outcomes, particularly in the context of other predisposing factors.

Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA.

The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a Kd of ~150 µM. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB.

Clustered charge-to-alanine mutagenesis of human respiratory syncytial virus L polymerase generates temperature-sensitive viruses.

Clustered charge-to-alanine mutagenesis was performed on the large (L) polymerase protein of human respiratory syncytial virus to identify charged residues in the L protein that are important for viral RNA synthesis and to generate temperature-sensitive viruses. Clusters of three, four, and five charged residues throughout the entire L protein were substituted with alanines. A minigenome replicon assay was used to determine the functions of the mutant L proteins and to identify mutations that caused temperature sensitivity by comparing the level of reporter gene expression at 39 and 33 degrees C. Charge-to-alanine mutations were introduced into an antigenomic cDNA derived from RSV A2 strain to recover infectious viruses. Of the 27 charge-to-alanine mutations, 17 recombinant viruses (63%) were obtained. Seven mutants (41%) exhibited small plaque morphologies and/or temperature-sensitive growth in tissue culture. To generate mutant viruses with more temperature-sensitive and attenuated phenotypes, several clusters of charge-to-alanine substitutions were combined. Five combination mutants were recovered that exhibited shut-off temperatures ranging from 36 to 39 degrees C in tissue culture and restricted replication in the respiratory tracts of cotton rats.

Evaluation of attenuation, immunogenicity and efficacy of a bovine parainfluenza virus type 3 (PIV-3) vaccine and a recombinant chimeric bovine/human PIV-3 vaccine vector in rhesus monkeys.

Restricted replication in the respiratory tract of rhesus monkeys is an intrinsic property of bovine parainfluenza virus type 3 (bPIV-3) strains. This host range phenotype of bPIV-3 has been utilized as a marker to evaluate the attenuation of bPIV-3 vaccines for human use. Two safety, immunogenicity and efficacy studies in primates evaluated and compared three human parainfluenza virus type 3 (hPIV-3) vaccine candidates: biologically derived bPIV-3, a plasmid-derived bPIV-3 (r-bPIV-3) and a chimeric bovine/human PIV-3 (b/hPIV-3). These studies also examined the feasibility of substituting Vero cells, cultured in the presence or absence of foetal bovine serum, for foetal rhesus lung-2 (FRhL-2) cells as the tissue culture substrate for the production of bPIV-3 vaccine. The results demonstrated that (i) Vero cell-produced bPIV-3 was as attenuated, immunogenic and efficacious as bPIV-3 vaccine grown in FRhL-2 cells, (ii) plasmid-derived bPIV-3 was as attenuated, immunogenic and efficacious as the biologically derived bPIV-3 and (iii) the b/hPIV-3 chimera displayed an intermediate attenuation phenotype and protected animals completely from hPIV-3 challenge. These results support the use of bPIV-3 vaccines propagated in Vero cells in human clinical trials and the use of b/hPIV-3 as a virus vaccine vector to express foreign viral antigens.