Oral Prednisone Use Following Primary Total Knee Arthroplasty Does Not Increase Infections, but can be Associated With Higher Risk for Medical and Surgical Complications.

BACKGROUND: Postoperative use of oral prednisone to augment the effect of multimodal pain regimens after total knee arthroplasty (TKA) has increased in popularity. However, data on the risks of its utilization, especially as it relates to infection, have been lacking. We tested the null hypothesis that perioperative prednisone use is not associated with the incidence of surgical and medical complications after TKA. METHODS: Using a national administrative claims database, we identified 949,555 patients undergoing primary TKA. We excluded patients who filled oral prednisone prescriptions within 90 days prior to surgery or between 90 and 364 days after surgery. Patients who had acute prednisone use were defined as those who filled prednisone prescriptions only within 30 days after surgery. Outcomes consisted of surgical and medical complications after TKA. Multivariable logistic regression models were used to evaluate the association between acute prednisone use and complications, adjusting for age, sex, region, insurance plan, and Elixhauser comorbidities. RESULTS: Patients in the acute prednisone cohort had greater adjusted odds of subsequent manipulation under anesthesia (adjusted odds ratio [OR] = 1.23 [95% confidence interval {CI}: 1.09 to 1.38]; P < .001) and lysis of adhesions (adjusted OR = 1.58 [95% CI: 1.02 to 2.33]; P = .03) compared to patients who did not have acute prednisone use. Patients who had acute prednisone use also had greater adjusted odds of acute kidney injury (adjusted OR = 1.47 [95% CI: 1.25 to 1.71]; P < .001) and pneumonia (adjusted OR = 4.04 [95% CI: 3.53 to 4.59]; P < .001). There was no increased incidence of infection. CONCLUSIONS: Prednisone use shortly following TKA may be associated with a higher incidence of certain surgical and medical complications, but without increased risk for infection. However, given these risks, the optimal patient profile for postoperative prednisone use remains to be defined.

Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans.

OBJECTIVE: Mutations in γ-aminobutyric acid (GABA) transporter 1 (GAT-1)-encoding SLC6A1 have been associated with myoclonic atonic epilepsy and other phenotypes. We determined the patho-mechanisms of the mutant GAT-1, in order to identify treatment targets. METHODS: We conducted whole-exome sequencing of patients with myoclonic atonic epilepsy (MAE) and characterized the seizure phenotypes and EEG patterns. We studied the protein stability and structural changes with homology modeling and machine learning tools. We characterized the function and trafficking of the mutant GAT-1 with 3H radioactive GABA uptake assay and confocal microscopy. We utilized different models including a knockin mouse and human astrocytes derived from induced pluripotent stem cells (iPSCs). We focused on astrocytes because of their direct impact of astrocytic GAT-1 in seizures. RESULTS: We identified four novel SLC6A1 variants associated with MAE and 2 to 4 Hz spike-wave discharges as a common EEG feature. Machine learning tools predicted that the variant proteins are destabilized. The variant protein had reduced expression and reduced GABA uptake due to endoplasmic reticular retention. The consistent observation was made in cortical and thalamic astrocytes from variant-knockin mice and human iPSC-derived astrocytes. The Slc6a+/A288V mouse, representative of MAE, had increased 5-7 Hz spike-wave discharges and absence seizures. INTERPRETATION: SLC6A1 variants in various locations of the protein peptides can cause MAE with similar seizure phenotypes and EEG features. Reduced GABA uptake is due to decreased functional GAT-1, which, in thalamic astrocytes, could result in increased extracellular GABA accumulation and enhanced tonic inhibition, leading to seizures and abnormal EEGs.

Intracellular Signaling Pathways Mediating Tyrosine Kinase Inhibitor Cardiotoxicity.

Tyrosine kinase inhibitors (TKIs) are used to treat several cancers; however, a myriad of adverse cardiotoxic effects remain a primary concern. Although hypertension (HTN) is the most common adverse effect reported with TKI therapy, incidents of arrhythmias (eg, QT prolongation, atrial fibrillation) and heart failure are also prevalent. These complications warrant further research toward understanding the mechanisms of TKI-induced cardiotoxicity. Recent literature has given some insight into the intracellular signaling pathways that may mediate TKI-induced cardiac dysfunction. In this article, we discuss the cardiotoxic effects of TKIs on cardiomyocyte function, signaling, and possible treatments.

Increasing Reoperations and Failures With Increasing BMI in Patients Undergoing 2-Stage Exchange for Infected Total Hip Arthroplasty.

BACKGROUND: While morbid obesity is associated with increased infection after total hip arthroplasty, little is known on the outcomes after 2-stage reimplantation for prosthetic joint infection (PJI) in this population. The purpose of this study is to evaluate the impact of morbid obesity (body mass index>40 kg/m2) on reinfection, postoperative complications, readmissions, and reoperations. METHODS: We conducted a retrospective review of 107 patients undergoing first time 2-stage reimplantation for PJI from 2013 to 2019. 18 patients (50% women) with body mass index>40 kg/m2 were identified. To minimize confounders, three propensity score matched cohorts were created, yielding 16 nonobese (<30 kg/m2), 16 obese (30-39.9 kg/m2), and 18 morbidly obese (>40 kg/m2) patients. Outcomes were compared using chi-square or Fisher's exact tests. All patients had minimum 12-month follow-up, with mean follow-up of 36.3, 30.1, and 40.0 months in the nonobese, obese, and morbidly obese cohorts, respectively. RESULTS: Compared with nonobese patients, morbidly obese patients had a higher rate of reinfection (0% vs 33%, P = .020 and higher likelihood of length of stay>4 days (19% vs 61%, P = .012). In addition, compared with nonobese and obese patients, morbidly obese patients had higher rate of return to the operating room for any reason (13% vs 19% vs 50%, respectively, P = .020). No differences between cohorts were found regarding complications, death, or revision surgery. CONCLUSION: Morbidly obese patients have significantly increased risk of reinfection and reoperation after 2-stage reimplantation for PJI when compared with obese and nonobese patients. These data can be used to counsel morbidly obese patients contemplating total hip arthroplasty and supports the notion of deferring arthroplasty in this population pending optimization.

Association of breast cancer with MRI background parenchymal enhancement: the IMAGINE case-control study.

BACKGROUND: Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. METHODS: The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years' experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. RESULTS: The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1/BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05-2.11; p = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92-2.27; p = 0.1). CONCLUSIONS: BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma.

BACKGROUND AND OBJECTIVES: Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. METHODS: We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were test-defined as pathogenic (PATH). RESULTS: Six hundred seventeen pCRC and 348 PM patients had similar gender (55% male) and age (median 59). PATHs were similar between PM and pCRC in KRAS, BRAF, SMAD2, SMAD4, and PTEN. pCRC PATHs were increased in APC (76% vs 48%, P < .01), ARID1A (29% vs 12%, P < .05), TP53 (72% vs 53%, P < .01), PIK3CA (22% vs 15%, P < .05), and FBXW7 (13% vs 7%, P < .01) compared with PM. Mucinous PM had more PATHs in GNAS (19% vs 8%, P = .032) while nonmucinous PM had more PATHs in BRAF (13% vs 8%, P = .027). Right-sided PM had decreased PATHs in APC (39% vs 68%, P < .0001), ARID1A (7% vs 38%, P < .004), and TP53 (48% vs 65%, P = .033) while there were no difference for left-sided PM. Nine percent of pCRC and 6% of PM were MSI-high (P = NS). There was no difference in TMB-high, TMB-intermediate, or TMB-low between PM and pCRC. CONCLUSIONS: PM have similar rates of KRAS mutation with increased PATHs in GNAS (mucinous) and BRAF (nonmucinous) compared to pCRC. No differences in MSI or TMB were identified between PM and pCRC tumors. These findings inform future study into the molecular profile of PM.

Correction to: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

In the original publication, the sixth author name was published incorrectly as Matthew Stein. The correct author name should read as Matthew K Stein.

Variation Among Pediatric Orthopaedic Surgeons When Diagnosing and Treating Pediatric and Adolescent Distal Radius Fractures.

BACKGROUND: Distal radius fractures are the most common injury in the pediatric population. The purpose of this study was to determine the variation among pediatric orthopaedic surgeons when diagnosing and treating distal radius fractures. METHODS: Nine pediatric orthopaedic surgeons reviewed 100 sets of wrist radiographs and were asked to describe the fracture, prescribe the type of treatment and length of immobilization, and determine the next follow-up visit. κ statistics were performed to assess the agreement with the chance agreement removed. RESULTS: Only fair agreement was present when diagnosing and classifying the distal radius fractures (κ=0.379). There was poor agreement regarding the type of treatment that would be recommended (κ=0.059). There was no agreement regarding the length of immobilization (κ=-0.004).Poor agreement was also present regarding when the first follow-up visit should occur (κ=0.088), whether or not new radiographs should be obtained at the first follow-up visit (κ=0.133), and if radiographs were necessary at the final follow-up visit (κ=0.163). Surgeons had fair agreement regarding stability of the fracture (κ=0.320).A subgroup analysis comparing various traits of the treatment immobilization showed providers only had a slight level of agreement on whether splint or cast immobilization should be used (κ=0.072). There was poor agreement regarding whether long-arm or short-arm immobilization should be prescribed (κ=-0.067).Twenty-three of the 100 radiographs were diagnosed as a torus/buckle fracture by all 9 surgeons. κ analysis performed on all the treatment and management questions showed that each query had poor agreement. CONCLUSIONS: The interobserver reliability of diagnosing pediatric distal radius fractures showed only fair agreement. This study demonstrates that there is no standardization regarding how to treat these fractures and the length of immobilization required for proper fracture healing. Better classification systems of distal radius fractures are needed that standardize the treatment of these injuries. LEVEL OF EVIDENCE: Level II.

Breast Cancer Screening and Diagnosis, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Breast Cancer Screening and Diagnosis have been developed to facilitate clinical decision making. This manuscript discusses the diagnostic evaluation of individuals with suspected breast cancer due to either abnormal imaging and/or physical findings. For breast cancer screening recommendations, please see the full guidelines on NCCN.org.

Clinical implementation of synthesized mammography with digital breast tomosynthesis in a routine clinical practice.

BACKGROUND: Most published studies evaluating digital breast tomosynthesis (DBT) included a separate 2-dimensional full-field digital mammogram (FFDM) for DBT screening protocols, increasing radiation from screening mammography. Synthesized mammography (SM) creates a 2-dimensional image from the DBT source data, and if used in place of FFDM, it reduces radiation of DBT screening. This study evaluated the implementation of SM + DBT in routine screening practice in terms of recall rates, cancer detection rates (CDR), % of minimal cancers, % of node-positive cancers, and positive predictive values (PPV). MATERIALS AND METHODS: A multivariate retrospective institutional analysis was performed on 31,979 women who obtained screening mammography (10/2013-12/2015) with cohorts divided by modality (SM + DBT, FFDM + DBT, and FFDM). We adjusted for comparison mammograms, age, breast density, and the interpreting radiologist. Recall type was analyzed for differences (focal asymmetry, asymmetry, masses, calcifications, architectural distortion). RESULTS: SM + DBT significantly decreased the recall rate compared to FFDM (5.52 vs. 7.83%, p < 0.001) with no differences in overall CDR (p = 0.66), invasive and/or in situ CDR, or percentages of minimal and node-negative cancers. PPV1 significantly increased with SM + DBT relative to FFDM (9.1 vs. 6.2%, p = 0.02). SM + DBT did not differ significantly in recall rate or overall CDR compared to FFDM + DBT. There were statistically significant differences in certain findings recalled by screening modality (e.g., focal asymmetries). CONCLUSIONS: SM + DBT reduces false positives compared to FFDM, while maintaining the CDR and other desirable audit outcome data. SM + DBT is more accurate than FFDM alone, and is a desirable alternative to FFDM + DBT, given the added benefit of radiation reduction.

Breast cancer screening of pregnant and breastfeeding women with BRCA mutations.

Screening recommendations for women with BRCA mutations include annual breast MRI starting at age 25, with annual mammogram added at age 30. The median age of childbearing in the US is age 28, therefore many BRCA mutation carriers will be pregnant or breastfeeding during the time when intensive screening is most important to manage their increased breast cancer risk. Despite this critical overlap, there is little evidence to guide clinicians on the appropriate screening for women with BRCA mutations during pregnancy or breastfeeding. Hormonal shifts that occur during pregnancy, the postpartum period, and breastfeeding result in changes to the breasts that may further complicate the sensitivity and specificity of screening modalities. We explore the safety and efficacy of available breast cancer screening modalities, including clinical breast exam, mammogram, breast MRI, and ultrasound among women with BRCA mutations who are pregnant or breastfeeding, providing recommendations from the most current published literature and expert opinion.

S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ.

NO is known to modulate calcium handling and cellular signaling in the myocardium, but key targets for NO in the heart remain unidentified. Recent reports have implied that NO can activate calcium/calmodulin (Ca(2+)/CaM)-dependent protein kinase II (CaMKII) in neurons and the heart. Here we use our novel sensor of CaMKII activation, Camui, to monitor changes in the conformation and activation of cardiac CaMKII (CaMKIIδ) activity after treatment with the NO donor S-nitrosoglutathione (GSNO). We demonstrate that exposure to NO after Ca(2+)/CaM binding to CaMKIIδ results in autonomous kinase activation, which is abolished by mutation of the Cys-290 site. However, exposure of CaMKIIδ to GSNO prior to Ca(2+)/CaM exposure strongly suppresses kinase activation and conformational change by Ca(2+)/CaM. This NO-induced inhibition was ablated by mutation of the Cys-273 site. We found parallel effects of GSNO on CaM/CaMKIIδ binding and CaMKIIδ-dependent ryanodine receptor activation in adult cardiac myocytes. We conclude that NO can play a dual role in regulating cardiac CaMKIIδ activity.

Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung.

Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes. 19 patients with small cell carcinoma of the breast were identified, median age was 58 years (range 37-79) and 42 % had metastatic disease at presentation; for comparison, 58 patients with small cell carcinoma of the lung were identified (66 [36-86], 65 % metastatic). By immunohistochemistry, 31 % of small cell carcinoma of the breast patients expressed ER, 13 % expressed PR, and 16 % expressed AR; small cell carcinoma of the lung patients expressed ER 0 %, PR 2 %, and AR 6 %. Small cell carcinoma of the breast and small cell carcinoma of the lung patients had similar patterns of other immunohistochemical expression (0 v 0 % PDL1, 50 v 42 % PD1, and 77 v 95 % TOP2A, respectively). All small carcinoma of the breast and small cell carcinoma of the lung patients were negative for HER2 and cMET amplification by in situ hybridization. Next generation sequencing revealed TP53 mutations in 75 % of patients both with small cell carcinoma of the breast and small cell carcinoma of the lung and PIK3CA mutations in 33 % of small cell carcinoma of the breast patients but no small cell carcinoma of the lung patients (Fisher's exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in small cell carcinoma of the breast patients and no other mutation occurred in over 10 % of small cell carcinoma of the lung patients except RB1 in 19 % (p = 0.31). Small cell carcinoma of the breast is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between small cell carcinoma of the breast and small cell carcinoma of the lung with the exception an increased incidence of PIK3CA mutations in small cell carcinoma of the breast, which may have therapeutic implications.

ß-adrenergic signaling inhibits Gq-dependent protein kinase D activation by preventing protein kinase D translocation.

RATIONALE: Both ß-adrenergic receptor (ß-AR) and Gq-coupled receptor (GqR) agonist-driven signaling play key roles in the events, leading up to and during cardiac dysfunction. How these stimuli interact at the level of protein kinase D (PKD), a nodal point in cardiac hypertrophic signaling, remains unclear. OBJECTIVE: To assess the spatiotemporal dynamics of PKD activation in response to ß-AR signaling alone and on coactivation with GqR-agonists. This will test our hypothesis that compartmentalized PKD signaling reconciles disparate findings of PKA facilitation and inhibition of PKD activation. METHODS AND RESULTS: We report on the spatial and temporal profiles of PKD activation using green fluorescent protein-tagged PKD (wildtype or mutant S427E) and targeted fluorescence resonance energy transfer-based biosensors (D-kinase activity reporters) in adult cardiomyocytes. We find that ß-AR/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of ß-AR/cAMP/PKA signaling on GqR-induced translocation and activation of PKD throughout the cardiomyocyte. We attribute these effects to direct, PKA-dependent phosphorylation of PKD-S427. We also show that phosphomimetic substitution of S427 likewise impedes GqR-induced PKD translocation and activation. In neonatal myocytes, S427E inhibits GqR-evoked cell growth and expression of hypertrophic markers. Finally, we show altered S427 phosphorylation in transverse aortic constriction-induced hypertrophy. CONCLUSIONS: ß-AR signaling triggers local nuclear signaling and inhibits GqR-mediated PKD activation by preventing its intracellular translocation. PKA-dependent phosphorylation of PKD-S427 fine-tunes the PKD responsiveness to GqR-agonists, serving as a key integration point for ß-adrenergic and Gq-coupled stimuli.

Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study.

BACKGROUND: Healthy volunteer wild-type influenza challenge models offer a unique opportunity to evaluate multiple aspects of this important virus. Such studies have not been performed in the United States in more than a decade, limiting our capability to investigate this virus and develop countermeasures. We have completed the first ever wild-type influenza A challenge study under an Investigational New Drug application (IND). This dose-finding study will lead to further development of this model both for A(H1N1)pdm09 and other strains of influenza. METHODS: Volunteers were admitted to an isolation unit at the National Institutes of Health Clinical Center for a minimum of 9 days. A reverse genetics, cell-based, Good Manufacturing Practice (GMP)-produced, wild-type A(H1N1)pdm09 virus was administered intranasally. Escalating doses were given until a dose was reached that produced disease in a minimum of 60% of volunteers. RESULTS: An optimal dose of 10(7) tissue culture infectious dose 50 was reached that caused mild to moderate influenza disease in 69% of individuals with mean viral shedding for 4-5 days and significant rises in convalescent influenza antibody titers. Viral shedding preceded symptoms by 12-24 hours and terminated 2-3 days prior to symptom resolution, indicating that individuals may be infectious before symptom development. As expected, nasal congestion and rhinorrhea were most common, but interestingly, fever was observed in only 10% of individuals. CONCLUSIONS: This study represents the first healthy volunteer influenza challenge model using a GMP-produced wild-type virus under an IND. This unique clinical research program will facilitate future studies of influenza pathogenesis, animal model validation, and the rapid, efficient, and cost-effective evaluation of efficacy of novel vaccines and therapeutics. Clinical Trials Registration.NCT01646138.

Psychological distress, job dissatisfaction, and somatic symptoms in office workers in 6 non-problem buildings in the Midwest.

BACKGROUND: Researchers examined office worker characteristics and reports of non-specific somatic symptoms in 6 non-problem buildings in the Midwestern United States. METHODS: We assessed office workers for demographic characteristics and somatic symptoms that occurred in the workplace. Sampling was conducted over a 1-week period in each building over 4 seasons. Our team administered the Medical Outcome Survey questionnaire, the Brief Symptom Inventory, and the Job Content Questionnaire to individuals at each site, comparing office workers reporting no symptoms to those reporting ≥4 symptoms. RESULTS: Self-reported nonspecific somatic symptoms were frequent in office workers in non-problem buildings. High symptom levels were associated with younger age, female sex, psychological distress, impaired quality of life, and poor job satisfaction. CONCLUSIONS: The findings suggest that office workers frequently report somatic symptoms they believe are related to the workplace even in buildings considered non-problematic. People with high symptom levels perceived as related to the workplace are psychologically distressed, have impaired quality of life, and feel dissatisfied and powerless in the workplace.

Punishing "Privilege": Antisemitic Hate Crime in Canada.

Both federal government and civil society organization data point to consistently rising incidents of antisemitic narratives and acts across Canada. In spite of this, antisemitic hate crime has not been the focus of any academic research here, some would argue because Jews are not typically thought to be an at-risk community. Rather, the Jewish community is thought to occupy a relatively privileged place in society which shields them from bias motivated attacks. Countering this narrative, our study, based in Ontario and Quebec, reveals that Jewish individuals and institutions are highly vulnerable to discursive, physical, and property violations. Many of those we spoke with felt embattled by the narrative attacks that rendered the community vulnerable to corollary physical attacks. Of particular significance are the enabling images of Jews that equate "Jewish privilege" with excessive power and control. We explore these themes, concluding with calls for strategies intended to counter hateful narratives.

Variable Efficacy of Tranexamic Acid in Geriatric Hip Fractures Treated With Arthroplasty Versus Cephalomedullary Nails.

INTRODUCTION: Geriatric hip fractures are associated with high rates of disability and mortality. Many of these patients require perioperative and postoperative allogeneic blood transfusions, which carry several noteworthy risks. A growing body of literature supports the efficacy of tranexamic acid (TXA) in geriatric hip fractures, without sufficient data examining which subgroups are likely to benefit the most. METHODS: In this study, we sought to evaluate whether TXA was associated with reduced blood loss and transfusions in a geriatric population undergoing hip fracture fixation at our institution during a 2-year period. The first year's data were collected in a retrospective fashion before the introduction of a quality control initiative encouraging TXA administration for all geriatric hip fractures. The second year's data were collected prospectively. A subgroup analysis was conducted for patients who underwent arthroplasties. RESULTS: Among the pooled cohort of patients undergoing surgery, TXA showed no benefit over control subjects for reducing blood loss or transfusion requirements. However, the subgroup of patients undergoing arthroplasty procedures showed a notable decrease in total blood loss and total units transfused during hospitalization. DISCUSSION: These results suggest that TXA may be most beneficial when targeted to arthroplasties performed for geriatric hip fractures.

Upregulation of proteasome activity in muscle RING finger 1-null mice following denervation.

Deletion of muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, leads to sparing of muscle mass following denervation. The purpose of this study was to test the hypothesis that muscle sparing in mice with a deletion of MuRF1 is due to the selective inhibition of the ubiquitin proteasome system. Activities of the 20S and 26S proteasomes, calpain and cathepsin L, were measured in the triceps surae muscles of wild-type (WT) and MuRF1-knockout (KO) mice at 3 and 14 d following denervation. In addition, fractional protein synthesis rates and differential gene expression were measured in WT and KO muscle. The major finding was that 20S and 26S proteasome activities were significantly elevated (1.5- to 2.5-fold) after 14 d of denervation in both WT and KO mice relative to control, but interestingly, the activities of both the 20S and 26S proteasome were significantly higher in KO than WT mice. Further, mRNA expression of MAFbx was elevated after 14 d of denervation in KO, but not WT, mice. These data challenge the conventional dogma that MuRF1 is controlling the degradation of only contractile proteins and suggest a role for MuRF1 in the global control of the ubiquitin proteasome system and protein turnover.

Jails, HIV testing, and linkage to care services: an overview of the EnhanceLink initiative.

Over 9 million persons in the United States (US) are admitted each year to jails. HIV prevalence among detainees is higher than the general population, which creates a public health need for linking HIV-infected detainees to services during jail and after release. The EnhanceLink initiative was funded as demonstration projects in 10 communities at 20 separate jails across the US. Grantees implemented and evaluated innovative models of HIV testing in jails and linkage of HIV-infected individuals to community services post release. In this paper, we describe services delivered with the EnhanceLink initiative. During 877,119 admission events, 210,267 inmates agreed to HIV testing and 822 new diagnoses of HIV were made. The majority of persons served with transitional services were previously diagnosed before the current incarceration. Cumulatively, 9,837 HIV+ persons were offered linkage and transitional services and 8,056 (82 %) accepted the offer. EnhanceLink demonstrated the feasibility of HIV testing in jail settings and provision of linkage services to enhance continuity of HIV care post-release.