Factors associated with oral anticoagulant prescription status among patients with a new diagnosis of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and increases stroke risk. Treatment with oral anticoagulants (OACs) may reduce this risk however many patients do not receive OAC therapy. This study aimed to use electronic health record data to identify newly diagnosed AF patients at high risk for stroke and not anticoagulated as well as factors associated with OAC prescription. HYPOTHESIS: Timely prescription of OACs among patients with newly diagnosed AF is poor. METHODS: We performed a retrospective study of patients with a new diagnosis of AF. We assessed stroke risk with the CHA2 DS2 -VASc score. The primary outcome was prescription of an OAC within 6 months following diagnosis. We used logistic regression to see how the odds of being prescribed an OAC differs for 17 independent variables. RESULTS: We identified 18 404 patients with a new diagnosis of AF. Among patients at high risk for stroke, 41.3% received an OAC prescription within 6 months. Male sex, Caucasian compared to African American race, stroke, obesity, congestive heart failure, vascular disorder, current antiplatelet, beta blocker, or calcium channel blocker prescription, and increasing CHA2 DS2 -VASc score were positively associated with receiving an OAC. Whereas anemia, renal dysfunction, liver dysfunction, antiarrhythmic drug use and increasing HAS-BLED score were negatively associated. CONCLUSIONS: Most newly diagnosed AF patients at high stroke risk do not receive an OAC prescription in the first 6 months following diagnosis. Our analysis suggests that patient sex, race, comorbidities, and additional prescriptions are associated with rates of OAC prescribing.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Biomarkers in Axial Spondyloarthritis: Observational Studies From the Program to Understand the Longterm Outcomes in Spondyloarthritis Registry.

OBJECTIVES: This study was conducted to assess the utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting radiographic sacroiliitis and active disease in axial spondyloarthritis (SpA) and to explore the association between use of a tumor necrosis factor inhibitor (TNFi) and these laboratory values compared with traditional inflammatory markers. METHODS: Observational data from the Program to Understand the Longterm Outcomes in Spondyloarthritis (PULSAR) registry were analyzed. We generated receiver operating characteristic curves to calculate laboratory cutoff values; we used these values in multivariable logistic regression models to identify associations with radiographically confirmed sacroiliitis and active disease. We also used logistic regression to determine the likelihood of elevated laboratory values after initiation of TNFi. RESULTS: Most study participants (n = 354) were White, male, and HLA-B27 positive. NLR (odds ratio [OR] 1.459, P = 0.034), PLR (OR 4.842, P < 0.001), erythrocyte sedimentation rate (OR 4.397, P < 0.001), and C-reactive protein (CRP) level (OR 2.911, P = 0.001) were independent predictors of radiographic sacroiliitis. Models that included PLR with traditional biomarkers performed better than those with traditional biomarkers alone. NLR (OR 6.931, P = 0.002) and CRP (OR 2.678, P = 0.004) were predictors of active disease, but the model that included both NLR and CRP performed better than CRP alone. TNFi use reduced the odds of elevated NLR (OR 0.172, P < 0.001), PLR (OR 0.073, P < 0.001), erythrocyte sedimentation rate (OR 0.319, P < 0.001), and CRP (OR 0.407, P < 0.001), but models that included NLR or PLR and traditional biomarkers performed best. CONCLUSIONS: These findings demonstrate an association between NLR and PLR and sacroiliitis and disease activity, with NLR and PLR showing response after TNFi treatment and adding useful clinical information to established biomarkers, thus perhaps assisting in management of axial SpA.

Mitochondrial Targeting of Amyloid-ß Protein Precursor Intracellular Domain Induces Hippocampal Cell Death via a Mechanism Distinct from Amyloid-ß.

BACKGROUND: Amyloid-ß (Aß) is a principal cleavage product of amyloid-ß protein precursor (AßPP) and is widely recognized as a key pathogenic player in Alzheimer's disease (AD). Yet, there is increasing evidence of a neurotoxic role for the AßPP intracellular domain (AICD) which has been proposed to occur through its nuclear function. Intriguingly, there is a γ-secretase resident at the mitochondria which could produce AICD locally. OBJECTIVE: We examined the potential of AICD to induce neuronal apoptosis when targeted specifically to the mitochondria and compared its mechanism of neurotoxicity to that of Aß. METHODS: We utilized transient transfection of HT22 neuronal cells with bicistronic plasmids coding for DsRed and either empty vector (Ires), Aß, AICD59, or mitochondrial-targeted AICD (mitoAICD) in combination with various inhibitors of pathways involved in apoptosis. RESULTS: AICD induced significant neuronal apoptosis only when targeted to the mitochondria. Apoptosis required functional mitochondria as neither Aß nor mitoAICD induced significant toxicity in cells devoid of mitochondrial DNA. Both glutathione and a Bax inhibitor protected HT22 cells from either peptide. However, inhibition of the mitochondrial permeability transition pore only protected from Aß, while pan-caspase inhibitors uniquely rescued cells from mitoAICD. CONCLUSION: Our results show that AICD displays a novel neurotoxic function when targeted to mitochondria. Moreover, mitoAICD induces apoptosis via a mechanism that is distinct from that of Aß. These findings suggest that AICD produced locally at mitochondria via organelle-specific γ-secretase could act in a synergistic manner with Aß to cause mitochondrial dysfunction and neuronal death in AD.

Fulminant Vasculitis Complicated by ST-Elevation Myocardial Infarction and Stroke.

Acute coronary syndrome is a rare complication of vasculitis. We present a case of fulminant medium-vessel vasculitis, most likely PAN, complicated by STEMI and stroke, that was successfully treated with percutaneous revascularization, high-quality stroke care, and immunosuppression. This case highlights the importance of prompt diagnosis and treatment of vasculitis and the recognition of coronary and cerebral ischemia as potentially serious complications.

Glycemic benefits with adherence to testosterone therapy in men with hypogonadism and type 2 diabetes mellitus.

BACKGROUND: While previous studies have demonstrated testosterone's beneficial effects on glycemic control in men with hypogonadism and Type 2 Diabetes, the extent to which these improvements are observed based on the degree of treatment adherence has been unclear. OBJECTIVES: To evaluate the effects of long-term testosterone therapy in A1C levels in men with Type 2 Diabetes Mellitus and hypogonadism, controlling for BMI, pre-treatment A1C, and age among different testosterone therapy adherence groups. MATERIALS AND METHODS: We performed a retrospective analysis of 1737 men with diabetes and hypogonadism on testosterone therapy for 5 years of data from 2008-2018, isolating A1C, lipid panels, and BMI results for analysis. Subjects were categorized into adherence groups based on quartiles of the proportion of days covered (> 75% of days, 51-75% of days, 26-50% of days and 0-25% of days), with >75% of days covered considered adherent to therapy. RESULTS: Pre-treatment median A1C was 6.8%. Post-treatment median A1C was 7.1%. The adherent group, >75%, was the only group notable for a decrease in A1C, with a median decrease of -0.2 (p = 0.0022). BMI improvement was associated with improved post-treatment A1C (p = 0.007). When controlling for BMI, age, and pre-treatment A1C, the >75% adherence group was associated with improved post-treatment A1C (p < 0.001). DISCUSSION: When controlling for all studied variables, testosterone adherence was associated with improved post-treatment A1C. The higher the initial A1C at the initiation of therapy, the higher the potential for lowering the patient's A1C with >75% adherence. Further, all groups showed some reduction in BMI, which may indicate that testosterone therapy may affect A1C independent of weight loss. CONCLUSION: Even when controlling for improved BMI, pre-treatment A1C, and age, testosterone positively impacted glycemic control in diabetes patients with hypogonadism, with the most benefit noted in those most adherent to therapy (>75%).

Fractures in patients with rheumatoid arthritis and end-stage renal disease.

Having rheumatoid arthritis (RA) or end-stage renal disease (ESRD) can lead to fractures. RA independently increases the risk of hip or other femur fracture in dialysis patients. Use of corticosteroids is a potentially modifiable risk factor for fractures among persons with RA and ESRD on dialysis. PURPOSE: Rheumatoid arthritis (RA) and end-stage renal disease (ESRD) both independently increase fracture risk; however, how RA and ESRD interplay to affect fracture risk is unknown. We aim to determine the association of RA with fracture in ESRD and identify risk factors for fracture in patients with RA and ESRD. METHODS: A retrospective cohort study was conducted using the United States Renal Data System (USRDS) to identify ESRD adults with and without a history of RA who initiated dialysis in 2005-2008. International Classification of Diseases, 9th Revision (ICD-9) codes were used to identify fractures following start of dialysis. Risk for incident fracture was compared between those with and without RA. Potential risk factors for fracture among persons with RA and ESRD were analyzed. RESULTS: There were 754 persons with ESRD and RA, of whom 126 (17%) had any incident fracture. In multivariable adjusted final models, among ESRD patients, RA was an independent risk factor for hip/femur fracture (RR 1.28, 95% CI 1.01-1.64). Among persons with RA and ESRD, in final models, only corticosteroid use was a significant risk factor for both any incident (RR 2.00, 95% CI 1.40-2.87) and hip/femur (RR 1.97, 95% CI 1.24-3.11) fracture. Those with higher body mass index had a lower relative risk of hip/femur fracture (RR 0.95, 95% CI 0.91-0.99). CONCLUSION: Among ESRD patients, those with RA have a 28% increased risk for hip or other femur fracture. Use of corticosteroids is a potentially modifiable risk factor for fractures among persons with RA and ESRD.

The cysteine-rich whey protein supplement, Immunocal®, preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact.

Traumatic brain injury (TBI) is a major public health problem estimated to affect nearly 1.7 million people in the United States annually. Due to the often debilitating effects of TBI, novel preventative agents are highly desirable for at risk populations. Here, we tested a whey protein supplement, Immunocal®, for its potential to enhance resilience to TBI. Immunocal® is a non-denatured whey protein preparation which has been shown to act as a cysteine delivery system to increase levels of the essential antioxidant glutathione (GSH). Twice daily oral supplementation of CD1 mice with Immunocal® for 28 days prior to receiving a moderate TBI prevented an ~ 25% reduction in brain GSH/GSSG observed in untreated TBI mice. Immunocal® had no significant effect on the primary mechanical injury induced by TBI, as assessed by MRI, changes in Tau phosphorylation, and righting reflex time or apnea. However, pre-injury supplementation with Immunocal® resulted in statistically significant improvements in motor function (beam walk and rotarod) and cognitive function (Barnes maze). We also observed a significant preservation of corpus callosum width (axonal myelination), a significant decrease in degenerating neurons, a reduction in Iba1 (microglial marker), decreased lipid peroxidation, and preservation of brain-derived neurotrophic factor (BDNF) in the brains of Immunocal®-pretreated mice compared to untreated TBI mice. Taken together, these data indicate that pre-injury supplementation with Immunocal® significantly enhances the resilience to TBI induced by a moderate closed head injury in mice. We conclude that Immunocal® may hold significant promise as a preventative agent for TBI, particularly in certain high risk populations such as athletes and military personnel.

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis.

AIM: To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS: Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs (DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics. RESULTS: Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events (-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events (+5.85 mg/dL, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events (-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (ß = -0.58, P = 0.01) and hydroxychloroquine (ß = -5.78, P = 0.01) use as predictors of lower post-medication-initiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure (ß = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events. CONCLUSION: No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

A Cystine-Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro by Preserving Cellular Glutathione.

Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal®) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing ß-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of γ-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases.

Mitochondrial glutathione transport is a key determinant of neuronal susceptibility to oxidative and nitrosative stress.

Mitochondrial oxidative stress significantly contributes to the underlying pathology of several devastating neurodegenerative disorders. Mitochondria are highly sensitive to the damaging effects of reactive oxygen and nitrogen species; therefore, these organelles are equipped with a number of free radical scavenging systems. In particular, the mitochondrial glutathione (GSH) pool is a critical antioxidant reserve that is derived entirely from the larger cytosolic pool via facilitated transport. The mechanism of mitochondrial GSH transport has not been extensively studied in the brain. However, the dicarboxylate (DIC) and 2-oxoglutarate (OGC) carriers localized to the inner mitochondrial membrane have been established as GSH transporters in liver and kidney. Here, we investigated the role of these carriers in protecting neurons from oxidative and nitrosative stress. Immunoblot analysis of DIC and OGC in primary cultures of rat cerebellar granule neurons (CGNs) and cerebellar astrocytes showed differential expression of these carriers, with CGNs expressing only DIC and astrocytes expressing both DIC and OGC. Consistent with these findings, butylmalonate specifically reduced mitochondrial GSH in CGNs, whereas both butylmalonate and phenylsuccinate diminished mitochondrial GSH in astrocytes. Moreover, preincubation with butylmalonate but not phenylsuccinate significantly enhanced susceptibility of CGNs to oxidative and nitrosative stressors. This increased vulnerability was largely prevented by incubation with cell-permeable GSH monoethylester but not malate. Finally, knockdown of DIC with adenoviral siRNA also rendered CGNs more susceptible to oxidative stress. These findings demonstrate that maintenance of the mitochondrial GSH pool via sustained mitochondrial GSH transport is essential to protect neurons from oxidative and nitrosative stress.