Citations

ObjectiveTotal knee arthroplasty (TKA) is a widely utilized and effective treatment option for end‐stage knee osteoarthritis (OA). Knee OA is more prevalent among women compared to men, but there are limited data on the sex differences in surgical outcomes after primary TKA.MethodsOur sample consisted of all primary TKAs performed in Pennsylvania during the fiscal year 2002. We used International Classification of Diseases, Ninth Revision, Clinical Modification codes to identify major complications and surgical revision. We used mixed‐effects logistic regression models to examine the associations between sex and all‐cause mortality, readmissions, and major surgical complications. We used proportional hazards models to assess the risk of surgical revision after index arthroplasty. We adjusted for race, age, hospital teaching status, hospital procedure volume, insurance status, and risk of mortality.ResultsIn 17,994 primary TKAs, there were 46 and 220 deaths at 30 days and 1 year, respectively. Compared to women, men had higher adjusted odds of 1‐year mortality (odds ratio [OR] 1.48 [95% confidence interval (95% CI) 1.13–1.94]) after primary TKA. The overall odds of most major 30‐day complications did not differ by sex except for surgical wound infections, which were higher in men compared to women (OR 1.31 [95% CI 1.08–1.60]); 30‐day readmission was higher in men (OR 1.25 [95% CI 1.10–1.43]). Men had significantly higher rates of revision of index knee arthroplasty at 5 years (hazard ratio 1.20 [95% CI 1.05–1.36]) compared to women.ConclusionThe higher rates of mortality, hospital readmissions, revision surgery, and wound infections in men undergoing elective primary TKA compared to women indicate there is a sex disparity in these outcomes.

Abstract Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

Background— The multicenter PROTECT AF study (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) was conducted to determine whether percutaneous left atrial appendage closure with a filter device (Watchman) was noninferior to warfarin for stroke prevention in atrial fibrillation. Methods and Results— Patients (n=707) with nonvalvular atrial fibrillation and at least 1 risk factor (age >75 years, hypertension, heart failure, diabetes, or prior stroke/transient ischemic attack) were randomized to either the Watchman device (n=463) or continued warfarin (n=244) in a 2:1 ratio. After device implantation, warfarin was continued for ≈45 days, followed by clopidogrel for 4.5 months and lifelong aspirin. Study discontinuation rates were 15.3% (71/463) and 22.5% (55/244) for the Watchman and warfarin groups, respectively. The time in therapeutic range for the warfarin group was 66%. The composite primary efficacy end point included stroke, systemic embolism, and cardiovascular death, and the primary analysis was by intention to treat. After 1588 patient-years of follow-up (mean 2.3±1.1 years), the primary efficacy event rates were 3.0% and 4.3% (percent per 100 patient-years) in the Watchman and warfarin groups, respectively (relative risk, 0.71; 95% confidence interval, 0.44%–1.30% per year), which met the criteria for noninferiority (probability of noninferiority >0.999). There were more primary safety events in the Watchman group (5.5% per year; 95% confidence interval, 4.2%–7.1% per year) than in the control group (3.6% per year; 95% confidence interval, 2.2%–5.3% per year; relative risk, 1.53; 95% confidence interval, 0.95–2.70). Conclusions— The “local” strategy of left atrial appendage closure is noninferior to “systemic” anticoagulation with warfarin. PROTECT AF has, for the first time, implicated the left atrial appendage in the pathogenesis of stroke in atrial fibrillation. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00129545.

ABSTRACT Adenovirus serotype 5 (Ad5) naturally infects the liver after intravenous injection, making it a candidate for hepatocyte-directed gene transfer. While Ad5 can be efficient, most of the dose is destroyed by liver Kupffer cells before it can reach hepatocytes. In contrast, Ad5 bearing the hexon from Ad6 (Ad5/6) evades Kupffer cells. While Ad5/6 dramatically increases hepatocyte transduction in BALB/c mice, it has surprisingly little effect on C57BL/6 mice. To determine the source of this strain-specific difference, the roles of Kupffer cells, liver sinusoidal endothelial cells (LSECs), hepatocytes, scavenger receptors, clotting factors, and immunoglobulins were analyzed. The numbers of Kupffer cells and LSECs, the level of clotting factor X, and hepatocyte infectibility did not differ between different strains of mice. In contrast, high levels of immunoglobulins correlated negatively with Ad5 liver transduction in different mouse strains. Removal of immunoglobulins by use of Rag-deficient mice restored Ad5 transduction to maximal levels. Removal of Kupffer cells by predosing or by testing in colony-stimulating factor knockout mice restored Ad5 transduction in the presence of immunoglobulins. Partial reconstitution of IgM in Rag mice resulted in significant reductions in liver transduction by Ad5 but not by Ad5/6. These data suggest a role for IgM-mediated clearance of Ad5 via Kupffer cells and may explain the mechanism by which Ad5/6 evades these cells. These mechanisms may play a vital role in Ad pharmacology in animals and in humans.

Background: Polypharmacy has been identified as a quality indicator, but no studies have been reported about the epidemiology of polypharmacy among hospital patients at discharge. Methods: Records of 142 family medicine patients aged ≥65 years who were discharged from the hospital during the period November 2008 to October 2009 were extracted. Forty-six of these patients were readmitted within 30 days and the remaining 96 not readmitted within 30 days. Polypharmacy was measured as >16 medications at dismissal. Independent variables related to person (use of medical care in the 12 months prior to hospitalization, number of high-risk diagnoses, and demographic characteristics), place (living situation at admission and disposition location), and time (month of admission). Chronic obstructive pulmonary disease, cancer, diabetes mellitus, congestive heart failure, and coronary artery disease were diagnoses determined to be high-risk. Results: Mean number of medications at dismissal was 13.5 and 23.2% of patients were prescribed more than 16 medications. No interactions were found between readmission status and any of the independent variables. Use of medical services in the previous year was not related to polypharmacy and no seasonal pattern was detected. Two or more high-risk diagnoses were independently related to polypharmacy (odds ratio [OR] = 4.75, confidence interval [CI] = 1.0-11.2, P = .00). Being discharged to a location with personal health services such as home care or a skilled nursing facility was also related to polypharmacy (OR = 3.07, CI = 1.3-7.2, P = .01). Conclusion: Drug reviews intended to reduce the rate of polypharmacy among discharged persons aged ≥65 years can be targeted at patients who have 2 or more high-risk diagnoses and at those discharged to receive personal health services either at home or in a convalescence facility.

Purpose: The purpose of this study was to compare continuity of care for family medicine patients using retail medicine clinics to continuity for patients not using retail clinics. Retail medicine clinics have become popular in some markets. However, their impact on continuity of care has not been studied. Methods: Electronic medical records of adult primary care patients seen in a large group practice in Minnesota in 2011 were analyzed for this study. Two randomly chosen groups of patients were selected (N = 400): those using 1 of 3 retail walk-in clinics staffed by nurse practitioners in addition to standard office care and a comparison group that only used standard office care. Continuity was measured as the percentage of visits that involved the primary care provider. We also compared patients who made zero visits to their primary care providers with those who made some visits to their primary care providers. Results: Continuity of care was lower for patients who used retail clinics than for patients who did not use retail clinics (0.17 vs 0.44, mean difference 0.27). The percentage of patients who made zero visits to their primary care providers was 54.5 for users of retail clinics versus 31.0 for those who did not use retail clinics. Conclusions: Continuity of care should be monitored as retail medicine continues to expand.

ABSTRACT We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)–PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma.