eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling.

Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.

Fostamatinib for the Treatment of Hospitalized Adults With Coronavirus Disease 2019: A Randomized Trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response, and immunothrombosis. Fostamatinib is a novel spleen tyrosine kinase inhibitor that we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with COVID-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. RESULTS: A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared with 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ±â€…0.3 vs -2.6 ±â€…0.4, P = .035) and the median length in the intensive care unit was 3 days in the fostamatinib group vs 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs 28, P = .027). There were trends toward more rapid reductions in C-reactive protein, D-dimer, fibrinogen, and ferritin levels in the fostamatinib group. CONCLUSION: For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared with placebo. These results warrant further validation in larger confirmatory trials. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov, NCT04579393.

The relationship between systemic inflammation and increased left ventricular mass is partly mediated by noncalcified coronary artery disease burden in psoriasis.

OBJECTIVE: Increased left ventricular (LV) mass is an important precursor to heart failure. Inflammation plays an important role in increasing LV mass. However, the contribution of subclinical coronary artery disease (CAD) to the inflammation-LV mass relationship is unknown. In subjects with psoriasis, a chronic inflammatory skin disease, we evaluated if systemic inflammation assessed by plasma glycoprotein A (GlycA) associated with LV mass measured on coronary CT angiography (CCTA). Additionally, we analyzed whether this relationship was mediated by early CAD assessed as noncalcified coronary burden (NCB). METHODS: We performed an observational longitudinal study of 213 subjects with psoriasis free of known cardiovascular disease, 189 of whom were followed over one year. All participants had GlycA measurements by nuclear magnetic resonance spectroscopy and LV mass and NCB quantified by CCTA. RESULTS: The cohort had a mean age of 50.3 (±12.9) years and 59% were male. There was moderate psoriasis severity and low cardiovascular risk. LV mass increased by GlycA tertiles [1st tertile:24.6 g/m2.7(3.8), 2nd tertile:25.5 g/m2.7(3.8), 3rd tertile:27.7 g/m2.7(5.5), p<0.001]. Both GlycA (ß=0.24, p = 0.001) and NCB (ß=0.50, p<0.001) associated with LV mass in models adjusted for age, sex, hypertension, hypertension therapy, lipid therapy, biologic therapy for psoriasis, waist:hip ratio, psoriasis disease duration and severity. In multivariable-adjusted mediation analyses, NCB accounted for 32% of the GlycA-LV mass relationship. Finally, over one year, change in NCB independently associated with change in LV mass (ß=0.25, p = 0.002). CONCLUSIONS: Both systemic inflammation and coronary artery NCB were associated with LV mass beyond cardiovascular risk factors in psoriasis. Furthermore, a substantial proportion of the inflammatory-LV mass relationship was mediated by NCB. These findings underscore the possible contribution of early coronary artery disease to the relationship between systemic inflammation and LV mass.

Metabolic syndrome and its factors are associated with noncalcified coronary burden in psoriasis: An observational cohort study.

BACKGROUND: Psoriasis is associated with a heightened risk of cardiovascular disease and higher prevalence of metabolic syndrome. OBJECTIVE: Investigate the effect of metabolic syndrome and its factors on early coronary artery disease assessed as noncalcified coronary burden by coronary computed tomography angiography in psoriasis. METHODS: This cross-sectional study consisted of 260 participants with psoriasis and coronary computed tomography angiography characterization. Metabolic syndrome was defined according to the harmonized International Diabetes Federation criteria. RESULTS: Of the 260 participants, 80 had metabolic syndrome (31%). The metabolic syndrome group had a higher burden of cardiometabolic disease, systemic inflammation, noncalcified coronary burden, and high-risk coronary plaque. After adjusting for Framingham risk score, lipid-lowering therapy, and biologic use, metabolic syndrome (ß = .31; P < .001) and its individual factors of waist circumference (ß = .33; P < .001), triglyceride levels (ß = .17; P = .005), blood pressure (ß = .18; P = .005), and fasting glucose (ß = .17; P = .009) were significantly associated with noncalcified coronary burden. After adjusting for all other metabolic syndrome factors, blood pressure and waist circumference remained significantly associated with noncalcified coronary burden. LIMITATIONS: Observational nature with limited ability to control for confounders. CONCLUSIONS: In psoriasis, individuals with metabolic syndrome had more cardiovascular disease risk factors, systemic inflammation, and noncalcified coronary burden. Efforts to increase metabolic syndrome awareness in psoriasis should be undertaken to reduce the heightened cardiovascular disease risk.

Association Among Noncalcified Coronary Burden, Fractional Flow Reserve, and Myocardial Injury in Psoriasis.

Background Myocardial infarction and premature death have been observed in patients with psoriasis. Although inflammation-driven accelerated atherosclerosis has been proposed as a mechanism, the relationship between subclinical noncalcified coronary burden (NCB), functional coronary flow impairment, and myocardial injury is unclear. Methods and Results In an ongoing longitudinal cohort study, 202 consecutive patients with psoriasis (168 at 1 year) underwent coronary computed tomography angiography to identify coronary plaque, quantify NCB, and calculate coronary fractional flow reserve by computed tomography. Serum high-sensitivity troponin-T (hs-cTn-T) was measured using a fifth-generation assay. Overall, patients were middle-aged, predominantly male, and low cardiovascular risk. A higher than median NCB associated with a positive hs-cTn-T (fully adjusted model [odds ratio (OR), 1.72; 95% CI, 1.10-2.69, P=0.018]) at baseline. Additionally, patients with a higher than median baseline NCB had higher odds of positive hs-cTn-T at 1 year in fully adjusted analyses (adjusted OR, 2.36; 95% CI, 1.47-3.79, P<0.001). Higher NCB was associated with a higher frequency of fractional flow reserve by computed tomography ≤0.80 (36.11% versus 25.11%, Pearson χ2=6.84, P=0.009, unadjusted OR, 2.09; 95% CI, 1.36-3.22, P<0.001) and higher frequency of a positive hs-cTn-T (54.36% versus 27.54%, Pearson χ2=32.23, P<0.001) in adjusted models (OR, 2.63; 95% CI, 1.56-4.42, P<0.001). Conclusions NCB was associated with hs-cTn-T at baseline as well as at 1 year. Furthermore, patients with high NCB had higher prevalence of fractional flow reserve by computed tomography ≤0.80 and a >2- fold higher odds of positive hs-cTn-T. These findings underscore the importance of early vascular disease in driving myocardial injury, and support conduct of myocardial perfusion studies to better understand these findings.

Chronic inflammation in psoriasis promotes visceral adiposity associated with noncalcified coronary burden over time.

BACKGROUNDPsoriasis is a chronic inflammatory skin disease associated with increased obesity, noncalcified coronary artery burden (NCB), and incident myocardial infarction. Here, we sought to assess the relationship among inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis.METHODSConsecutive psoriasis patients underwent coronary CT angiography to quantify NCB and abdominal CT to calculate VAT at baseline (n = 237), 1 year (n = 176), and 4 years (n = 50).RESULTSPatients with high levels of high-sensitivity C-reactive protein (hs-CRP) had significantly greater visceral adiposity (17,952.9 ± 849.2 cc3 vs. 13370.7 ± 806.8 cc3, P < 0.001) and noncalcified coronary burden (1.26 ± 0.03 vs. 1.07 ± 0.02 mm2) than those with low levels of hs-CRP. Those with higher levels of VAT had more systemic inflammation (hs-CRP, median [IQR], 2.5 mg/L [1.0-5.3 mg/L] vs. 1.2 mg/L [0.6-2.9 mg/L]), with approximately 50% higher NCB (1.42 ± 0.6 mm2 vs. 0.91 ± 0.2 mm2, P < 0.001). VAT associated with NCB in fully adjusted models (ß = 0.47, P < 0.001). At 1-year follow-up, patients who had worsening hs-CRP had an increase in VAT (14,748.7 ± 878.1 cc3 to 15,158.7 ± 881.5 cc3; P = 0.03), whereas those who had improved hs-CRP improved their VAT (16,876.1 ± 915.2 cc3 to 16310.4 ± 889.6 cc3; P = 0.04). At 1 year, there was 10.3% reduction in NCB in those who had decreased VAT (ß = 0.26, P < 0.0001), which persisted in a subset of patients at 4 years (ß = 0.39, P = 0.003).CONCLUSIONSInflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its effect on early atherogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778569.FUNDINGThis study was supported by the National Heart, Lung, and Blood Institute Intramural Research Program (HL006193-05), the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (no. 2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and Elsevier as well as private donors.

Treatment of Psoriasis With Biologic Therapy Is Associated With Improvement of Coronary Artery Plaque Lipid-Rich Necrotic Core: Results From a Prospective, Observational Study.

BACKGROUND: Lipid-rich necrotic core (LRNC), a high-risk coronary plaque feature assessed by coronary computed tomography angiography, is associated with increased risk of future cardiovascular events in patients with subclinical, nonobstructive coronary artery disease. Psoriasis is a chronic inflammatory condition that is associated with increased prevalence of high-risk coronary plaque and risk of cardiovascular events. This study characterized LRNC in psoriasis and how LRNC modulates in response to biologic therapy. METHODS: Consecutive biologic naïve psoriasis patients (n=209) underwent coronary computed tomography angiography at baseline and 1-year to assess changes in LRNC using a novel histopathologically validated software (vascuCAP Elucid Bioimaging, Boston, MA) before and after biologic therapy over 1 year. RESULTS: Study participants were middle-aged, predominantly male with similar cardiometabolic and psoriasis status between treatment groups. In all participants at baseline, LRNC was associated with Framingham risk score (ß [standardized ß]=0.12 [95% CI, 0.00-0.15]; P=0.045), and psoriasis severity (ß=0.13 [95% CI, 0.01-0.26]; P=0.029). At 1-year, participants receiving biologic therapy had a reduction in LRNC (mm2; 3.12 [1.99-4.66] versus 2.97 [1.84-4.35]; P=0.028), while those who did not receive biologic therapy over 1 year demonstrated no significant change with nominally higher LRNC (3.12 [1.82-4.60] versus 3.34 [2.04-4.74]; P=0.06). The change in LRNC was significant compared with that of the nonbiologic treated group (ΔLRNC, -0.22 mm2 versus 0.14 mm2, P=0.004) and remained significant after adjusting for cardiovascular risk factors and psoriasis severity (ß=-0.09 [95% CI, -0.01 to -0.18]; P=0.033). CONCLUSIONS: LRNC was associated with psoriasis severity and cardiovascular risk factors in psoriasis. Additionally, there was favorable modification of LRNC in those on biologic therapy. This study provides evidence of potential reduction in LRNC with treatment of systemic inflammation. Larger, longer follow-up prospective studies should be conducted to understand how changes in LRNC may translate into a reduction in future cardiovascular events in psoriasis.

Application of machine learning to determine top predictors of noncalcified coronary burden in psoriasis: An observational cohort study.

BACKGROUND: Psoriasis is associated with elevated risk of heart attack and increased accumulation of subclinical noncalcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well-characterized data sets. OBJECTIVE: In this study, we used machine learning algorithms to determine the top predictors of noncalcified coronary burden by CCTA in psoriasis. METHODS: The analysis included 263 consecutive patients with 63 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative. The random forest algorithm was used to determine the top predictors of noncalcified coronary burden by CCTA. We evaluated our results using linear regression models. RESULTS: Using the random forest algorithm, we found that the top 10 predictors of noncalcified coronary burden were body mass index, visceral adiposity, total adiposity, apolipoprotein A1, high-density lipoprotein, erythrocyte sedimentation rate, subcutaneous adiposity, small low-density lipoprotein particle, cholesterol efflux capacity and the absolute granulocyte count. Linear regression of noncalcified coronary burden yielded results consistent with our machine learning output. LIMITATION: We were unable to provide external validation and did not study cardiovascular events. CONCLUSION: Machine learning methods identified the top predictors of noncalcified coronary burden in psoriasis. These factors were related to obesity, dyslipidemia, and inflammation, showing that these are important targets when treating comorbidities in psoriasis.

Association of Biologic Therapy With Coronary Inflammation in Patients With Psoriasis as Assessed by Perivascular Fat Attenuation Index.

Importance: Psoriasis is a chronic inflammatory skin disease associated with increased coronary plaque burden and cardiovascular events. Biologic therapy for psoriasis has been found to be favorably associated with luminal coronary plaque, but it is unclear whether these associations are attributable to direct anti-inflammatory effects on the coronary arteries. Objective: To investigate the association of biologic therapy with coronary inflammation in patients with psoriasis using the perivascular fat attenuation index (FAI), a novel imaging biomarker that assesses coronary inflammation by mapping spatial changes of perivascular fat composition via coronary computed tomography angiography (CCTA). Design, Setting, and Participants: This prospective cohort study performed from January 1, 2013, through March 31, 2019, analyzed changes in FAI in patients with moderate to severe psoriasis who underwent CCTA at baseline and at 1 year and were not receiving biologic psoriasis therapy at baseline. Exposures: Biologic therapy for psoriasis. Main Outcomes and Measures: Perivascular FAI mapping was performed based on an established method by a reader blinded to patient demographics, visit, and treatment status. Results: Of the 134 patients (mean [SD] age, 51.1 [12.1] years; 84 [62.5%] male), most had low cardiovascular risk by traditional risk scores (median 10-year Framingham Risk Score, 3% [interquartile range, 1%-7%]) and moderate to severe skin disease. Of these patients, 82 received biologic psoriasis therapy (anti-tumor necrosis factor α, anti-interleukin [IL] 12/23, or anti-IL-17) for 1 year, and 52 did not receive any biologic therapy and were given topical or light therapy (control group). At baseline, 46 patients (27 in the treated group and 19 in the untreated group) had a focal coronary atherosclerotic plaque. Biologic therapy was associated with a significant decrease in FAI at 1 year (median FAI -71.22 HU [interquartile range (IQR), -75.85 to -68.11 HU] at baseline vs -76.09 HU [IQR, -80.08 to -70.37 HU] at 1 year; P < .001) concurrent with skin disease improvement (median PASI, 7.7 [IQR, 3.2-12.5] at baseline vs 3.2 [IQR, 1.8-5.7] at 1 year; P < .001), whereas no change in FAI was noted in those not receiving biologic therapy (median FAI, -71.98 [IQR, -77.36 to -65.64] at baseline vs -72.66 [IQR, -78.21 to -67.44] at 1 year; P = .39). The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents, including anti-tumor necrosis factor α (median FAI, -71.25 [IQR, -75.86 to -66.89] at baseline vs -75.49 [IQR, -79.12 to -68.58] at 1 year; P < .001) and anti-IL-12/23 or anti-IL-17 therapy (median FAI, -71.18 [IQR, -75.85 to -68.80] at baseline vs -76.92 [IQR, -81.16 to -71.67] at 1 year; P < .001). Conclusions and Relevance: In this study, biologic therapy for moderate to severe psoriasis was associated with reduced coronary inflammation assessed by perivascular FAI. This finding suggests that perivascular FAI measured by CCTA may be used to track response to interventions for coronary artery disease.

Racial Misclassification in Mortality Records Among American Indians/Alaska Natives in Oklahoma From 1991 to 2015.

OBJECTIVE: The primary purpose of this study was to compare age-adjusted mortality rates before and after linkage with Indian Health Service records, adjusting for racial misclassification. We focused on differences in racial misclassification by gender, age, geographic differences, substate planning districts, and cause of death. Our secondary purpose was to evaluate time trends in misclassification from 1991 to 2015. DESIGN: Retrospective, descriptive study. SETTING: Oklahoma. PARTICIPANTS: Persons contained in the Oklahoma State Health Department Vital Records. MAIN OUTCOME MEASURES: To evaluate the age-adjusted mortality ratio pre- and post-Indian Health Service record linkage (misclassification rate ratio) and to evaluate the overall trend of racial misclassification on mortality records measured through annual percent change (APC) and average annual percent change (AAPC). RESULTS: We identified 2 stable trends of racial misclassification upon death for American Indians/Alaska Natives (AI/ANs) from 1991 to 2001 (APC: -0.2%; 95% confidence interval: -1.4% to 1.0%) and from 2001 to 2005 (APC: -6.9%; 95% confidence interval: -13.7% to 0.4%). However, the trend identified from 2005 to 2015 decreased significantly (APC: -1.4%; 95% confidence interval: -2.5% to -0.2%). For the last 5 years available (2011-2015), the racial misclassification adjustment resulted in higher mortality rates for AI/ANs reflecting an increase from 1008 per 100 000 to 1305 per 100 000 with the linkage process. There were an estimated 3939 AI/ANs in Oklahoma who were misclassified as another race upon death in those 5 years, resulting in an underestimation of actual AI/AN deaths by nearly 29%. CONCLUSIONS: An important result of this study is that misclassification is improving; however, this effort needs to be maintained and further improved. Continued linkage efforts and public access to linked data are essential throughout the United States to better understand the burden of disease in the AI/AN population.

Genomic Research and American Indian Tribal Communities in Oklahoma: Learning From Past Research Misconduct and Building Future Trusting Partnerships.

Research misconduct and consequential harms have been inflicted upon American Indian/Alaska Native communities for decades. To protect their people and culture and to retain oversight over research, many Native communities have established tribal health research and institutional review boards. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study showcases a successful, trusting research collaboration with tribal nations and academic investigators in Oklahoma. In 2006, the TODAY Study investigators proposed a modification of the study protocol to collect biological specimens from participants for genomic analyses and indefinite storage. Partnering American Indian tribal nations elected not to participate in the genomics collection and repository proposal. Reasons included 1) protection of cultural values, 2) concerns regarding community anonymity, 3) a potential threat to tribal services eligibility, 4) broad informed consent language, and 5) vague definitions of data access and usage. The nations believed the proposed genomics analyses presented a risk of harm to their people and nations without clear benefit. Since the 2006 proposal and the advancement of genomics research, many tribal communities in Oklahoma, appreciating the potential benefits of genomic research, are developing policies regarding oversight of/access to data and biological specimens to mitigate risks and provide members and communities with opportunities to participate in safe and meaningful genomic research.

Managing emerging transnational public health security threats: lessons learned from the 2014 West African Ebola outbreak.

BACKGROUND: Pandemics pose significant security/stability risks to nations with fragile infrastructures. We evaluated characteristics of the 2014 West African Ebola outbreak to elucidate lessons learned for managing transnational public health security threats. METHODS: We used publically available data to compare demographic and outbreak-specific data for Guinea, Sierra Leone, and Liberia, including key indicator data by the World Health Organization. Pearson correlation statistics were calculated to compare country-level infrastructure characteristics with outbreak size and duration. RESULTS: Hospital bed density was inversely correlated with longer EVD outbreak duration (r = - 0.99). Country-specific funding amount allocations were more likely associated with number of incident cases than the population at-risk or infrastructure needs. Key indicators demonstrating challenges for Guinea included: number of unsafe burials, percent of EVD-positive samples, and days between symptom onset and case hospitalization. Sierra Leone's primary key indicator was the number of districts with ≥1 security incident. Liberia controlled their outbreak before much of the key-indicator data were collected. CONCLUSION: Many of the country-level factors, particularly the WHO key indicators were associated with controlling the epidemic. The infrastructure of countries affected by communicable diseases should be assessed by international political and public health leaders.

Cancer among American Indians - Identifying Priority Areas in Oklahoma.

BACKGROUND: We describe and compare cancer incidence and mortality among American Indians (AI/ANs) and whites in nine Indian Health Service (IHS) Service Units in Oklahoma. METHODS: Using data from the Oklahoma Central Cancer Registry and the web-based OK2SHARE database, we obtained age-adjusted cancer incidence rates from 1997 to 2012 and cancer mortality rates from 1999 to 2009 for AI/ANs and whites in Oklahoma. We examined differences in primary site, percentage of late stage diagnoses, and trends over time. RESULTS: AI/ANs consistently had higher cancer incidence and mortality compared to whites in Oklahoma. The magnitude of disparity for cancer incidence and mortality varied by IHS Service Unit and by gender. The top three cancer sites were the same for all Service Units. The percentage of late stage diagnosis also varied by region. CONCLUSIONS: We identify priority areas where cancer disparity challenges exist among AI/ANs in Oklahoma.

Prevalence and Mortality of Melanoma in Oklahoma Among Racial Groups, 2000-2008.

INTRODUCTION: This study assessed the period prevalence (2000-2008) and mortality rates of melanoma, in Oklahoma, among different racial/ethnic strata. METHODS: We analyzed incident cases of melanoma from 2000-2008 from the Oklahoma Central Cancer Registry and determined disease duration using Kaplan-Meier survival analysis to calculate period prevalence of melanoma in Oklahoma. Using a series of Chi-Square tests, we compared period prevalence and mortality rates among the racial groups and compared mortality between Oklahoma and the US. RESULTS: White non-Hispanics in Oklahoma have the highest period prevalence (p<0.0001) among the racial strata. American Indian or Alaska Native (AI/AN) individuals have the second highest period prevalence in Oklahoma (p<0.0001). Furthermore, white non-Hispanics (p<0.0001) and AI/AN individuals (p=0.0003) in Oklahoma had higher mortality rates compared to the US. CONCLUSIONS: There are disparities in the prevalence and mortality of melanoma among the AI/AN population in Oklahoma, and prevention and education programs should focus on this population.

Reoperation rates for symptomatic nonunions in posterior cervical (subaxial) fusions with and without bone morphogenetic protein in a cohort of 1158 patients.

OBJECTIVE: Bone morphogenetic protein (BMP) was first approved in 2002 for use in single-level anterior lumbar fusions as an alternative to iliac crest grafts. Subsequent studies have concluded that BMP provides superior fusions rates and therefore reduces reoperations for nonunions. The purpose of this study was to determine the reoperation rates for symptomatic nonunions in posterior cervical (subaxial) spinal fusions with and without the use of BMP and to determine if the nonunion rates are statistically significantly different between the two groups. METHODS: Between January 2009 and September 2013, the authors identified 1158 posterior cervical spinal fusion cases in the subaxial spine (C2-7) from a large spine registry (Kaiser Permanente). Patient characteristics, diagnoses, operative times, lengths of stay, and reoperations were extracted from the registry. Reoperations for symptomatic nonunions were adjudicated via chart review. Logistic regression was conducted to produce estimates of odds ratios (OR) and 95% confidence intervals (CIs). Kaplan-Meier curves for the non-BMP and BMP groups were generated and compared using the log-rank test. RESULTS: In this cohort there were 1158 patients (19.3% with BMP) with a median follow up of 1.7 years (interquartile range [IQR] 0.7-2.9 years) and median duration to operative nonunion of 0.63 years (IQR 0.44-1.57 years). Kaplan-Meier curves showed no significant difference in reoperation rates for nonunions using the log-rank test (p = 0.179). In a subset of patients with more than 1 year of follow-up, 788 patients were identified (22.5% with BMP) with a median follow-up duration of 2.5 years (IQR 1.7-3.4 years) and a median time to operative nonunion of 0.73 years (IQR 0.44-1.57 years). There was no statistically significant difference in the symptomatic operative nonunion rates for posterior cervical (subaxial) fusions with BMP compared with non-BMP (1.1% vs. 0.7%; crude OR 1.73, 95% CI 0.32-9.55, p = 0.527) for more than 1 year of follow-up. CONCLUSIONS: This study presents the largest series of patients using BMP in posterior cervical (subaxial) spinal fusions. Reoperation rates for symptomatic nonunions with more than 1 year of follow-up were found to be 1.1% with BMP and 0.7% without BMP. There was no significant difference in the reoperation rates for symptomatic nonunions with or without BMP.

Reoperation Rates for Symptomatic Nonunions in Anterior Cervical Fusions From a National Spine Registry.

STUDY DESIGN: A retrospective cohort study with chart review. OBJECTIVE: To determine the reoperation rates for symptomatic nonunions for 1-level, 2-level, and 3-level anterior cervical discectomies and fusions (ACDFs) from a national spine registry. SUMMARY OF BACKGROUND DATA: There is very little data reported in the literature on reoperation rates for symptomatic nonunions after ACDFs. The reported nonunion rates are primarily based on radiographical evidence, although some of these may be asymptomatic. Similarly, there may be symptomatic patients with nonunions who elect not to have a reoperation. We think, however, data from a national spine registry provide a realistic and unbiased assessment of routine cervical spine fusion care and represent a heterogeneous population with varied indications and surgical techniques and are best suited to determine reoperations for symptomatic nonunions. METHODS: Using data from a Spine Implant Registry developed at a large integrated health care system (Kaiser Permanente), patients with ACDFs between January 2009 and December 2012 with 2-year follow-up were identified. Patient characteristics, admitting diagnosis, and number of levels fused were extracted from the registry. Reoperations for symptomatic nonunions from the index spinal procedure were identified by chart review. RESULTS: A cohort of 1054 patients with more than 2 years of follow-up were found to have reoperations for nonunions of 0.2%, 2.9%, and 6.5% for 1-level, 2-level, and 3-level ACDFs, respectively. CONCLUSION: A large cohort of ACDF patients with more than 2 years of follow-up had reoperations for nonunion rates significantly lower than reported in the literature for radiographical nonunions. We think our data add to the literature an important parameter (reoperations for nonunion rates) and provide useful information for patients, spine surgeons, and health care payers.

Risk Factors Associated With 30-day Readmissions After Instrumented Spine Surgery in 14,939 Patients: 30-day readmissions after instrumented spine surgery.

STUDY DESIGN: A retrospective review of instrumented spine registry from an integrated US healthcare system. OBJECTIVE: Investigate the 30-day readmission rate and risk factors after instrumented spine surgery. SUMMARY OF BACKGROUND DATA: Published readmission rates range from 2% to over 20%. We were interested in learning which patients were at greatest risk, when did readmissions occur, and why. METHOD: 30-day readmission rates were determined for 14,939 patients after an index spine procedure between 1/2009 and 3/2013. Data were analyzed with descriptive statistics, univariate, and multivariate logistic regression analysis. RESULT: The average age of the cohort was 59 (SD = 13.4) and 52% were female. The 30-day readmission rate was 5.5% (821/14,939). The temporal pattern for readmission was: 17% (140) at week 1, 48% (394) at week 2, 72% (591) at week 3, and 100% (821) at week 4. The leading causes were wound complications (infection, hematoma, dehiscence, seroma), sepsis, pain management, pneumonia, and pulmonary emboli/deep venous thrombosis. In a multivariate model, readmission risk factors were: malignancy (OR 2.99, 95% CI: 1.56, 5.73), operative time more than 400 minutes (OR 2.59, 95% CI: 1.66, 4.02), operative time 300-399 minutes (OR 2.33, 95% CI: 1.54-3.52), hospital stay 6-10 days (OR 2.03, 95% CI: 1.31-3.14), hospital stay more than 10 days (OR 1.85, 95% CI: 1.1, -3.08), surgical complications (OR 1.67, 95% CI: 1.18, 2.36), operative time 200-299 (OR 1.52, 95% CI: 1.04, 2.22), depression (OR 1.48, 95% CI: 1.14, 1.93), rheumatoid arthritis (OR 1.45, 95% CI: 1.05, 2.01), deficiency anemia (OR 1.30, 95% CI: 1.05, 1.61), and hypothyroidism (OR 1.29, 95% CI: 1.01, 1.64). CONCLUSION: Surgical complications (dural tear, deep infections, superficial infections, epidural hematoma), malignancy, lengthy operative times, and lengthy initial hospitalizations are all risk factors for 30-day readmission. These findings should be considered during preoperative assessment and surgical planning. LEVEL OF EVIDENCE: 3.

Asociación entre niveles de proteína C-reactiva y óxido nítrico con el pronóstico de pacientes con infarto cerebral agudo / Association of C-reactive protein and nitric oxide levels with the prognosis of acute ischemic stroke

Introducción: La inflamación y alteraciones en la biodisponibilidad del óxido nítrico (NO) han sido involucradas en la fisiopatología de la enfermedad cerebrovascular. Objetivo: El objetivo del estudio fue determinar el valor pronóstico de la medición de metabolitos del NO y marcadores inflamatorios en pacientes con infarto cerebral agudo. Materiales y métodos: Se incluyeron 158 pacientes con diagnóstico de infarto cerebral agudo en un estudio observacional de cohorte. Entre 48 y 72 horas del inicio de los síntomas se tomó una muestra de sangre para determinación del perfil bioquímico, marcadores inflamatorios (PCR, IL1-β, IL6, TNF-α) y nitritos/nitratos plasmáticos. Se realizó seguimiento durante 2 años para determinar la aparición de un nuevo evento (infarto cerebral, infarto de miocardio, falla cardiaca) o muerte de origen vascular. Un análisis de regresión multivariada de Cox permitió determinar los factores asociados independientemente con el desenlace. Resultados: La edad promedio fue 70,5 ± 12,8 años. El 39,2% de los sujetos incluidos presentó el desenlace durante los primeros 24 meses de seguimiento. Los niveles de PCR > 12 mg/L (HR 2,22, IC 95% 1,07-4,59) y el puntaje > 13 en la escala NIHSS al ingreso (HR 2,81 IC 95% 1,46-5,41) se encontraron significativamente asociados con mayor riesgo de presentar un nuevo evento. La combinación de niveles de PCR < 12 mg/L y nitritos/nitratos < 35,5 µmol/L se identificó como un factor protector (HR 0,21, IC 95% 0,06-0,71). Conclusión: Este estudio sugiere que la determinación de nitritos/nitratos en conjunto con los niveles de PCR puede ser de utilidad para estratificar el riesgo de nuevos eventos en pacientes con infarto cerebral agudo.

Introduction: Inflammation and alterations in the bioavailability of nitric oxide (NO) have been involved in the pathophysiology of cerebrovascular disease. Objective: The aim of the study was to determine the prognostic value of measuring NO metabolites and inflammatory markers in patients with acute ischemic stroke. Materials and methods: A total of 158 patients with acute ischemic stroke were included in an observational cohort study. Between 48 and 72 hours post admission, a fasting blood sample was taken to determine the biochemical profile, inflammatory markers (CRP, IL1-β, IL6, TNF-α) and nitrites/nitrates plasma levels. The cohort's follow-up was conducted for two years to determine the occurrence of a new event (stroke, myocardial infarction, heart failure) or death of vascular origin. Comparisons between groups were made using the log-rank test. A Cox multivariate regression analysis permitted to determine factors independently associated with the outcome. Result: The mean age was 70.5 ± 12.8 years. 39.2% of the subjects presented the outcome during the first 24 months of follow-up. CRP levels > 12 mg/L (HR 2.22, 95% CI 1.07-4.59) and a score > 13 on the NIHSS scale at admission (HR 2.81 95% CI 1.46-5.41) were significantly associated with an increased risk of a new event. The combination of CRP levels < 12 mg/L and nitrites/nitrates levels < 35.5 mmol/L was identified as a protective factor (HR 0.21, 95% CI 0.06-0.71). Conclusion: This study demonstrates that the determination of CRP and NOx levels could be beneficial in clinical practice to stratify the risk of future events or death of vascular origin in acute ischemic stroke patients.