Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.

Ubiquitination is one of the most common post-translational modifications in eukaryotic cells. Depending on the architecture of polyubiquitin chains, substrate proteins can meet different cellular fates, but our understanding of how chain linkage controls protein fate remains limited. UBL-UBA shuttle proteins, such as UBQLN2, bind to ubiquitinated proteins and to the proteasome or other protein quality control machinery elements and play a role in substrate fate determination. Under physiological conditions, UBQLN2 forms biomolecular condensates through phase separation, a physicochemical phenomenon in which multivalent interactions drive the formation of a macromolecule-rich dense phase. Ubiquitin and polyubiquitin chains modulate UBQLN2's phase separation in a linkage-dependent manner, suggesting a possible link to substrate fate determination, but polyubiquitinated substrates have not been examined directly. Using sedimentation assays and microscopy we show that polyubiquitinated substrates induce UBQLN2 phase separation and incorporate into the resulting condensates. This substrate effect is strongest with K63-linked substrates, intermediate with mixed-linkage substrates, and weakest with K48-linked substrates. Proteasomes can be recruited to these condensates, but proteasome activity towards K63-linked and mixed linkage substrates is inhibited in condensates. Substrates are also protected from deubiquitinases by UBQLN2-induced phase separation. Our results suggest that phase separation could regulate the fate of ubiquitinated substrates in a chain-linkage dependent manner, thus serving as an interpreter of the ubiquitin code.

Avoiding Urinary Catheterization in Patients Undergoing Atrial Fibrillation Catheter Ablation.

PURPOSE: Indwelling urinary catheters are commonly inserted when administering general anesthesia. However, there are significant risks to routine IUC insertion. We compared urinary and other outcomes in a population of patients undergoing atrial fibrillation (AF) ablation with or without IUC. METHODS: This was a single center, retrospective review of patients undergoing AF ablation. Patients were identified by procedure codes and patient health characteristics and outcome data were manually extracted from electronic health records. The primary composite endpoint was 7-day periprocedural urinary outcomes including cystitis, dysuria, hematuria, urethral damage, or urinary retention. RESULTS: 404 patients were included in the study, 297 with IUC and 107 without IUC. Uncatheterized patients were less likely to have congestive heart failure (CHF) (31.8% vs 43.4%; P = 0.039) and had a shorter procedure length (4.2 vs 4.9 hours; P < 0.001) with less fluid administered (1485 vs 2040 mL; P < 0.001). No urinary complications occurred in the uncatheterized group versus 14 in the catheterized group (P = 0.026). 3 patients in the uncatheterized group developed serious infections versus none in the catheterized group (P = 0.018). There was no incidence of death and no statistically significant difference in readmission in the 30 days after procedure. CONCLUSIONS: There were no urinary complications in 107 patients who received no IUC during AF ablation. Avoiding bladder catheters during AF ablation procedures may lower incidence of adverse urinary complications without adding substantial risk of urinary retention.

Metabolic syndrome is associated with increased cardiac morbidity after infrainguinal bypass surgery irrespective of the use of cardiovascular risk-modifying agents.

BACKGROUND: The burden of metabolic syndrome (MetS) is increasing in the United States and is pervasive among patients with peripheral arterial disease. Whereas MetS has been implicated in the development of all types of cardiovascular disease and adverse outcomes after vascular interventions, little is known about how MetS influences perioperative outcomes of lower extremity bypass surgery and whether any negative effects can be modified by use of cardiovascular risk-modifying medications. METHODS: We used the National Surgical Quality Improvement Program vascular procedure-targeted database to capture patients undergoing infrainguinal bypass surgery between 2011 and 2015. We defined MetS using the modified MetS criteria: concomitant diabetes, hypertension, and body mass index >30 kg/m2. We used multivariable logistic regression analyses to examine the association between MetS and 30-day postoperative morbidity and mortality. We also examined whether preoperative aspirin, statin, and beta blockade modify the effects of MetS on 30-day postoperative outcomes. RESULTS: Of 10,053 patients who underwent infrainguinal bypass, 16% (1693) met criteria for MetS. After adjusting for covariates, MetS was significantly (P ≤ .05) associated with higher odds of postoperative myocardial infarction (odds ratio [OR], 1.66), infection (OR, 1.76), renal dysfunction (OR, 2.42), and length of stay (0.34 days). Within the MetS subgroup, there were no significant associations between use of preoperative cardiovascular risk-modifying agents and postoperative outcomes, with the exception of beta blockade and an increase in length of stay (0.33 days). CONCLUSIONS: Patients with MetS undergoing infrainguinal bypass surgery are at an increased risk of postoperative complications, including myocardial infarction. This elevated risk persists despite medical therapy with preoperative aspirin, statin, and beta blockade.

Blood Management Strategies to Reduce Transfusions After Elective Lower-Extremity Joint Arthroplasty Surgeries: One Tertiary Care Hospital's Early Experience With an Alternative Payment Model-a Total Joint "Bundle".

Blood loss associated with lower-extremity total joint arthroplasty (TJA) often results in anemia and the need for red blood cell transfusions (RBCTs). This article reports on a quality improvement initiative aimed at improving blood management strategies in patients undergoing TJA. A multifaceted intervention (preoperative anemia assessment, use of tranexamic acid, discouragement of autologous preoperative blood collection, restrictive RBCT protocols) was implemented. The results were stratified into 3 intervention periods: 1, pre; 2, peri; and 3, post. Fractional logistic regression was used to describe differences between various intervention periods. During the study period, 2511 patients underwent TJA. Compared with the preintervention period, there was 81.8% decrease in total units of RBCT during the postintervention period. Using activity-based costing (~$1000/unit), the annualized saving in RBC expenditure was $480 000. A multidisciplinary approach can be successful and sustainable in reducing RBCT and its associated costs for patients undergoing TJA.

Experience with Designing and Implementing a Bundled Payment Program for Total Hip Replacement.

BACKGROUND: Bundled payments, also known as episode-based payments, are intended to contain health care costs and promote quality. In 2011 a bundled payment pilot program for total hip replacement was implemented by an integrated health care delivery system in conjunction with a commercial health plan subsidiary. In July 2015 the Centers for Medicare & Medicaid Services (CMS) proposed the Comprehensive Care for Joint Replacement Model to test bundled payment for hip and knee replacement. METHODS: Stakeholders were identified and a structure for program development and implementation was created. An Oversight Committee provided governance over a Clinical Model Subgroup and a Financial Model Subgroup. RESULTS: The pilot program included (1) a clinical model of care encompassing the period from the preoperative evaluation through the third postoperative visit, (2) a pricing model, (3) a program to share savings, and (4) a patient engagement and expectation strategy. Compared to 32 historical controls-patients treated before bundle implementation-45 post-bundle-implementation patients with total hip replacement had a similar length of hospital stay (3.0 versus 3.4 days, p=.24), higher rates of discharge to home or home with services than to a rehabilitation facility (87% versus 63%), similar adjusted median total payments ($22,272 versus $22,567, p=.43), and lower median posthospital payments ($704 versus $1,121, p=.002), and were more likely to receive guideline-consistent care (99% versus 95%, p=.05). DISCUSSION: The bundled payment pilot program was associated with similar total costs, decreased posthospital costs, fewer discharges to rehabilitation facilities, and improved quality. Successful implementation of the program hinged on buy-in from stakeholders and close collaboration between stakeholders and the clinical and financial teams.

Femoral revision with a high offset long stem femoral component.

In this retrospective study, we evaluated the aspetic loosening rate and initial result of an extensively hypoxyapatite-coated high offset (127°) titanium femoral component in 27 consecutive femoral revisions. Fourteen men and 12 women (mean age, 68 years) were followed for 2 to 7 years. Preoperative, 3 month, 6 month, and yearly follow-ups included Harris Hip Scores and radiographic analysis. In this study group, the femoral stem length was 155 to 205 mm and the distal stem diameter was 12 to 20 mm. Extended trochanteric osteotomies were necessary on 7 cases. At a mean 53 months follow-up, there were no loose femoral components (ie, bone ingrown in all cases) and no subsequent femoral stem revisions. Thus far, this high offset stem has demonstrated an excellent rate of stable bone fixation.

Acetabular revision with the Contour antiprotrusio cage: 2- to 5-year followup.

The Contour cage introduced in 1999 was designed to improve fixation and provide a surface for bone ongrowth. To determine whether the rates of radiographic loosening and/or revision have been reduced with the Contour design, we retrospectively reviewed the medical records and radiographs of 29 patients (average age, 68.1 years) undergoing 31 acetabular revisions with a Contour cage. The minimum followup was 24 months (mean 30 months, range, 24-58 months). Based on the Paprosky classification, two hips were Type 2B, seven were Type 3A, and 22 were Type 3B. Two hips (7%) were revised for loosening; one of these two was also infected. An additional five hips (16%) had signs of radiographic loosening. The mean Harris hip score improved from 45 to 80; functional scores improved less than the pain scores. Only 14 hips (45%) had an excellent or good clinical result and three of these 14 hips had radiographic signs of loosening; presuming these three hips eventually fail, only 35% of the hips had a good or excellent result. We found an association between number of previous surgeries and radiographic loosening and revision. Our data suggest the Contour cage offers little advantage over other antiprotrusio cages and highlight the substantial limitations of current methods available for treating patients with extensive acetabular bone loss.