Low predictive power of comorbidity indices identified for mortality after acute arthroplasty surgery undertaken for femoral neck fracture.

AIMS: Our aim was to examine the Elixhauser and Charlson comorbidity indices, based on administrative data available before surgery, and to establish their predictive value for mortality for patients who underwent hip arthroplasty in the management of a femoral neck fracture. PATIENTS AND METHODS: We analyzed data from 42 354 patients from the Swedish Hip Arthroplasty Register between 2005 and 2012. Only the first operated hip was included for patients with bilateral arthroplasty. We obtained comorbidity data by linkage from the Swedish National Patient Register, as well as death dates from the national population register. We used univariable Cox regression models to predict mortality based on the comorbidity indices, as well as multivariable regression with age and gender. Predictive power was evaluated by a concordance index, ranging from 0.5 to 1 (with the higher value being the better predictive power). A concordance index less than 0.7 was considered poor. We used bootstrapping for internal validation of the results. RESULTS: The predictive power of mortality was poor for both the Elixhauser and Charlson comorbidity indices (concordance indices less than 0.7). The Charlson Comorbidity Index was superior to Elixhauser, and a model with age and gender was superior to both indices. CONCLUSION: Preoperative comorbidity from administrative data did not predict mortality for patients with a hip fracture treated by arthroplasty. This was true even if association on group level existed.

Multi-state analysis of hemi- and total hip arthroplasty for hip fractures in the Swedish population-Results from a Swedish national database study of 38,912 patients.

INTRODUCTION: Hip fractures are a common problem of the elderly population with significant mortality and morbidity. The choice between total hip arthroplasty (THA) and hemiarthroplasty depends on multiple factors including comorbidity. The Swedish Hip Arthroplasty Register (SHAR) provides a unique opportunity to study mortality and revision rates in this population. Linkage with government databases allow for in-depth research into the factors that influence risk of revision surgery and death in the hip fracture patient. PATIENTS AND METHODS: Data was linked between SHAR, Statistics Sweden and the National Board of Health and Welfare. Data was collected on 38,912 patients who received a fracture-related hip arthroplasty between 2005 and 2012. A multistate analysis was performed and three states were identified: primary hip surgery and alive (state 1), revision after primary hip surgery (state 2) and death (state 3). These were marking points in the longitudinal outcome study. RESULTS: 38,912 patients who received an arthroplasty for an acute hip fracture were included. By the end of the study period 1309 (3.4%) of these patients underwent a revision and 17,365 (45.1%) patients died. Patients with THA had a reduced risk of death from primary operation compared to hemiarthroplasty (HR = 0.49) and a decreased revision risk (HR = 0.69). Female patients had a statistically significant reduced mortality (HR = 0.6) compared to men. There was no statistically significant difference in risk of revision surgery between direct lateral and posterior approach. CONCLUSION: We identified an influence of type of surgery, sex, age and Elixhauser Comorbidity Index (ECI) on risk of revision and mortality. Males, greater comorbidity burden and older patients had higher mortality risks. The posterior approach did not have a significant influence on revision risk. Further research could include all patients who had reoperation(s) to further strengthen our findings. Patients who had a THA had lower revision rate and mortality. The latter is likely due to selection.

Sorting for storage in myeloid cells of nonmyeloid proteins and chimeras with the propeptide of myeloperoxidase precursor.

During formation of polymorphonuclear neutrophils, proteins are synthesized for storage in granules. Whereas sorting of proteins into distinct subtypes of cytoplasmic granules may reflect the coordinated expression of the proteins contained in them, still the mechanism(s) for the retrieval of proteins from the constitutive secretion is unknown. To investigate the mechanisms of retrieval, nonmyeloid secretory proteins were expressed in myeloid cell lines, and their subcellular fate was assessed. The contribution of the propeptide (MPOpro) of the myeloperoxidase (MPO) precursor was investigated by determining the fate of chimeras containing MPOpro. The nonmyeloid protein alpha(1)-microglobulin (alpha(1)-m) was targeted to storage organelles in 32D cells and colocalized with the lysosomal marker LAMP-1, whereas soluble TNF receptor 1 (sTNFR1) was secreted without granule targeting. Fusion of MPOpro to alpha(1)-m delayed exit from endoplasmic reticulum (ER), but subsequent targeting to dense organelles was indistinguishable from that of alpha(1)-m alone. Fusion proteins between MPOpro and sTNFR1 or green fluorescent protein expressed in myeloid 32D, K562, or PLB-985 cells did not associate stably with calreticulin or calnexin, molecular chaperones that normally interact transiently with the MPO precursor, but were still efficiently retained in the ER followed by degradation. We conclude that normally secreted, nonmyeloid proteins can be targeted efficiently to storage organelles in myeloid cells, that myeloid cells selectively target some proteins for storage but not others, and that MPOpro may contribute to the prolonged ER retention of the MPO precursor independent of the ER-molecular chaperones calreticulin and calnexin.

Structural requirements for intracellular processing and sorting of bactericidal/permeability-increasing protein (BPI): comparison with lipopolysaccharide-binding protein.

The bactericidal/permeability-increasing protein (BPI), which is stored in the azurophil granules of neutrophils, and the circulating lipopolysaccharide-binding protein (LBP) share the same structure. Both bind lipopolysaccharide of gram-negative bacteria through their amino-terminal domains. The carboxy-terminal domain of BPI promotes bacterial attachment to phagocytes, whereas the corresponding domain of LBP delivers lipopolysaccharide to monocytes/macrophages. Our aim was to investigate the role of the amino-and carboxy-terminal domains of BPI and LBP for sorting and storage in myeloid cells after transfection of cDNA to two rodent hematopoietic cell lines. Full-length BPI and LBP were both targeted for storage in these cells. Deletion of the carboxy-terminal half of BPI resulted in storage followed by degradation while the reciprocal deletion of the amino-terminal half led to retention in the endoplasmic reticulum for proteasomal degradation. Chimeras between halves of BPI and LBP were also targeted for storage, but those containing carboxy-terminal BPI had the highest stability, again indicating a role for the carboxy-terminal domain of BPI in protection against degradation. Therefore, we propose a critical stability function for the hydrophobic carboxy-terminal domain of BPI during intracellular sorting for storage while the amino-terminal domain may confer targeting for storage.

Processing and targeting of granule proteins in human neutrophils.

Neutrophils contain an assembly of granules destined for regulated secretion, each granule type with distinct constituents formed before terminal differentiation. The earliest granules are designated azurophil (primary), followed in time by specific (secondary), and gelatinase granules as well as secretory vesicles. Transcription factors regulate the genes for the granule proteins to ensure that expression of the gene products to be stored in different organelles is separated in time. Similar to lysosomal enzymes, many granule proteins, in particular those of the heterogeneous azurophil granules, are trimmed by proteolytic processing into mature proteins. Rodent myeloid cell lines have been utilized for research on the processing and targeting of human granule proteins after transfection of cDNA. Results from extensive work on the hematopoietic serine proteases of azurophil granules, employing in vitro mutagenesis, indicate that both an immature and a mature conformation are compatible with targeting for storage in granules. On the other hand, the amino-terminal propeptide of myeloperoxidase facilitates both the export from the endoplasmic reticulum and targeting for storage in granules. Similarly, targeting of defensins rely on an intact propeptide. The proteolytic processing into mature granule protein is most commonly a post-sorting event. Mis-sorting of specific granule proteins into azurophil or lysosome-like granules can result in premature activation and degradation, but represents a potential for manipulating the composition and function of neutrophil granules.