Cerebral Oximetry During Adult Cardiac Surgery Is Associated With Improved Postoperative Outcomes.

OBJECTIVE: To examine the association/effect of intraoperative cerebral oximetry (CeOx) on major organ morbidity and mortality (MOMM) after adult cardiac surgery. DESIGN: A retrospective, multicenter cohort study. SETTING: Patients treated at any hospital within the Society of Thoracic Surgeons Adult Cardiac Surgery Database between July 1, 2011, and December 31, 2016, with a 30-day postoperative follow-up. PARTICIPANTS: Individuals ≥18 years old undergoing isolated coronary artery bypass graft (CABG) or valve repair or replacement, or any combination of procedures with cardiopulmonary bypass. INTERVENTIONS: Intraoperative CeOx. MEASUREMENTS AND MAIN RESULTS: MOMM includes operative mortality, stroke, renal failure, prolonged mechanical ventilation, deep sternal wound infection, or reoperation for any reason within 30 days. Of 1.19 million patients who met inclusion criteria within 1,180 facilities, ∼30% (n = 361,124) received CeOx versus nonrecipients (n = 838,675) with similar baseline patient characteristics. Using a propensity score-based 1:1 greedy matching method, 99.7% of CeOx recipients (n = 360,285) were matched with nonrecipients. The rates of MOMM were lower with versus without CeOx. The absolute risk reduction translated to a number needed to treat of 227 patients (95% CI: 166-363, p < 0.0001). In sensitivity analyses of prespecified subgroups, the benefit was strongest among patients undergoing aortic valve repair or replacement ± CABG (more than 7 fewer MOMM events per 1,000, p < 0.0001). However, intensive care unit stay >72 hours was higher with CeOx. CONCLUSION: Intraoperative cerebral oximetry is associated with less major organ morbidity and mortality after adult cardiac surgery. A large-scale clinical trial is warranted, given that desaturation is common and correctable.

Risk of Postoperative Renal Failure in Radical Nephrectomy and Nephroureterectomy: A Validated Risk Prediction Model.

INTRODUCTION: The study aimed to construct and validate a risk prediction model for incidence of postoperative renal failure (PORF) following radical nephrectomy and nephroureterectomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database years 2005-2014 were used for the derivation cohort. A stepwise multivariate logistic regression analysis was conducted, and the final model was validated with an independent cohort from the ACS-NSQIP database years 2015-2017. RESULTS: In cohort of 14,519 patients, 296 (2.0%) developed PORF. The final 9-factor model included age, gender, diabetes, hypertension, BMI, preoperative creatinine, hematocrit, platelet count, and surgical approach. Model receiver-operator curve analysis provided a C-statistic of 0.79 (0.77, 0.82; p < 0.001), and overall calibration testing R2 was 0.99. Model performance in the validation cohort provided a C-statistic of 0.79 (0.76, 0.81; p < 0.001). CONCLUSION: PORF is a known risk factor for chronic kidney disease and cardiovascular morbidity, and is a common occurrence after unilateral kidney removal. The authors propose a robust and validated risk prediction model to aid in identification of high-risk patients and optimization of perioperative care.

The Adult Cardiac Anesthesiology Section of STS Adult Cardiac Surgery Database: 2020 Update on Quality and Outcomes.

The Society of Cardiovascular Anesthesiologists, in partnership with The Society of Thoracic Surgeons, has developed the Adult Cardiac Anesthesiology Section of the Adult Cardiac Surgery Database. The goal of this landmark collaboration is to advance clinical care, quality, and knowledge, and to demonstrate the value of cardiac anesthesiology in the perioperative care of cardiac surgical patients. Participation in the Adult Cardiac Anesthesiology Section has been optional since its inception in 2014 but has progressively increased. Opportunities for further growth and improvement remain. In this first update report on quality and outcomes of the Adult Cardiac Anesthesiology Section, we present an overview of the clinically significant anesthesia and surgical variables submitted between 2015 and 2018. Our review provides a summary of quality measures and outcomes related to the current practice of cardiothoracic anesthesiology. We also emphasize the potential for addressing high-impact research questions as data accumulate, with the overall goal of elucidating the influence of cardiac anesthesiology contributions to patient outcomes within the framework of the cardiac surgical team.

MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models.

The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.

Association of Both High and Low Left Ventricular Ejection Fraction With Increased Risk After Coronary Artery Bypass Grafting.

BACKGROUND: While reduced left ventricular ejection fraction (LVEF) is a known risk factor for complications after coronary artery bypass grafting (CABG), the relevance of higher LVEF values has not been established. Currently, most risk stratification tools consider LVEF values above a certain point as normal. However, since this does not account for insufficient ventricular filling or increased adrenergic tone, higher values may have clinical significance. To improve our understanding of this situation, we investigated the relationship of preoperative LVEF values with short- and long-term outcomes after CABG using a strategy that allowed for the identification of nonlinear relationships. We hypothesised that both higher and lower values are independently associated with increased postoperative complications and death in this population. METHODS: We performed a single-centre retrospective cohort study of patients undergoing isolated CABG surgery. All patients had a preoperative measurement of their LVEF. Surgery involving mitral valve repair was excluded in order to eliminate the impact of mitral regurgitation. The primary outcome was long-term mortality; secondary outcomes included atrial fibrillation, operative mortality, and a composite outcome including any postoperative adverse event. Fractional polynomial equations were used to model the relationship between LVEF and outcomes so we could account for nonlinear relationships if present. Adjustments for confounders were made using multivariable logistic regression and Cox models. RESULTS: A total of 7,932 subjects were included in the study. After adjusting for patient and surgical characteristics, LVEF remained associated with the primary outcome as well as the composite outcome of any postoperative adverse event. Both these relationships were best described by a J-shaped curve given that higher LVEF values were associated with increased risk, albeit not as high has lower values. Regarding long-term mortality, individuals with a preoperative LVEF of 60% demonstrated the longest survival. A statistically significant relationship was not found between LVEF and operative mortality or atrial fibrillation after adjustment for confounders. CONCLUSIONS: Higher preoperative LVEF values may be associated with increased risk for patients undergoing CABG surgery. Future studies are needed to better characterise this phenotype.

Outcomes following revascularization with radial artery bypass grafts: Insights from the PREVENT-IV trial.

BACKGROUND: The optimal role of radial artery grafts in coronary artery bypass grafting (CABG) remains uncertain. The purpose of this study was to examine angiographic and clinical outcomes following CABG among patients who received a radial artery graft. METHODS: Patients in the angiographic cohort of the PREVENT-IV trial were stratified based upon having received a radial artery graft or not during CABG. Baseline characteristics and 1-year angiographic and 5-year clinical outcomes were compared between patients. RESULTS: Of 1,923 patients in the angiographic cohort of PREVENT-IV, 117 received a radial artery graft. These patients had longer surgical procedures (median 253 vs 228 minutes, P < .001) and had a greater number of grafts placed (P < .0001). Radial artery grafts had a graft-level failure rate of 23.0%, which was similar to vein grafts (25.2%) and higher than left internal mammary artery grafts (8.3%). The hazard of the composite clinical outcome of death, myocardial infarction, or repeat revascularization was similar for both cohorts (adjusted hazard ratio 0.896, 95% CI 0.609-1.319, P = .58). Radial graft failure rates were higher when used to bypass moderately stenotic lesions (<75% stenosis, 37% failure) compared with severely stenotic lesions (≥75% stenosis, 15% failure). CONCLUSIONS: Radial artery grafts had early failure rates comparable to saphenous vein and higher than left internal mammary artery grafts. Use of a radial graft was not associated with a different rate of death, myocardial infarction, or postoperative revascularization. Despite the significant potential for residual confounding associated with post hoc observational analyses of clinical trial data, these findings suggest that when clinical circumstances permit, the radial artery is an acceptable alternative to saphenous vein and should be used to bypass severely stenotic target vessels.

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice.

Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1ß, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance.

Role of nutritional indices in predicting outcomes of vascular surgery.

BACKGROUND: Malnutrition is frequent among vascular surgery patients, given their age, chronic comorbidities, and poor functional status, and it is believed to increase their operative risk. We aimed to assess the combined use of recent significant weight loss (>10% body mass) and serum albumin levels as a nutritional status index to predict outcomes. METHODS: We analyzed vascular surgery data from the American College of Surgeons National Surgical Quality Improvement Program database (2005-2012; N = 238,082) to compare operative death (in-hospital and 30-day operative death) across eight nutritional status groups based on weight loss (yes/no) and albumin category: very low albumin level (VL-Alb; <2.50 g/dL), low albumin level (L-Alb; 2.50-3.39 g/dL), normal albumin level (N-Alb; 3.40-4.39 g/dL), and high albumin level (H-Alb; 4.40-5.40 g/dL). Risk-adjusted odds ratios (AOR) with 95% confidence intervals were estimated by multivariable logistic regression (N-Alb [no weight loss], reference). RESULTS: The study population included 113,936 patients for whom albumin level was available (age, 67 ± 13 years; 60.2% male). Operative death was documented in 5160 (4.53%) patients. The eight-category nutritional status was more predictive of operative death than age alone (C statistic, 0.74 vs 0.63). A high discrimination multivariable model for operative death was derived (C statistic, 0.851). Low albumin level was associated with increased death that worsened in case of weight loss: VL-Alb + WL, AOR = 3.83 (3.03-4.83); VL-Alb, AOR = 3.36 (3.06-3.69); L-Alb + WL, AOR = 2.46 (1.98-3.05); and L-Alb, AOR = 1.99 (1.84-2.15). Weight loss was associated with increased death even if albumin level was normal: N-Alb + WL, AOR = 1.77 (1.34-2.35); and H-Alb + WL, AOR = 1.91 (0.69-5.31). H-Alb was protective (AOR = 0.65 [0.55-0.76]). CONCLUSIONS: Nutritional status predicts outcomes of vascular surgery. Serum albumin level and weight loss should be incorporated in patients' risk stratification.

Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.

Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic.

Optimal management of radial artery grafts in CABG: Patient and target vessel selection and anti-spasm therapy.

The current literature on radial artery grafting is reviewed focusing on the optimal deployment of radial artery grafts in coronary artery bypass surgery with specific attention to the selection of patients and target vessels for radial artery grafting.

The effect of completeness of revascularization during CABG with single versus multiple arterial grafts.

INTRODUCTION: Incomplete coronary revascularization is associated with suboptimal outcomes. We investigated the long-term effects of Incomplete, Complete, and Supra-complete revascularization and whether these effects differed in the setting of single-arterial and multi-arterial coronary artery bypass graft (CABG). METHODS: We analyzed 15-year mortality in 7157 CABG patients (64.1 ± 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (single-arterial) or with at least one additional arterial graft (multi-arterial) and were grouped based on a completeness of revascularization index (CRI = number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRI ≤ -1 [N = 320;4.5%]); Complete (CRI = 0 [N = 2882;40.3%]; reference group); and two Supra-complete categories (CRI = +1[N = 3050; 42.6%]; CRI ≥ + 2 [N = 905; 12.6%]). Risk-adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression. RESULTS: Incomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval] = 1.53 [1.29-1.80]), those undergoing single-arterial CABG (AHR = 1.27 [1.04-1.54]) and multi-arterial CABG (AHR = 2.18 [1.60-2.99]), as well as in patients with 3-Vessel (AHR = 1.37 [1.16-1.62]) and, to a lesser degree, with 2-Vessel (AHR = 1.67 [0.53-5.23]) coronary disease. Supra-complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRI = +1] = 0.94 [0.87-1.03]); AHR [CRI ≥ +2] = 0.74 [0.64-0.85]), and was driven by a significantly decreased mortality risk in single-arterial CABG (AHR [CRI = +1] = 0.90 [0.81-0.99]; AHR [CRI ≥ +2] = 0.64 [0.53-0.78]); and 3-Vessel disease patients (AHR [CRI = +1] = 0.94 [0.86-1.04]; and AHR [CRI ≥ +2] = 0.75 [0.63-0.88]) with no impact in multi-arterial CABG (AHR [CRI = +1] = 1.07 [0.91-1.26]; AHR [CRI ≥ +2] = 0.93 [0.73-1.17]). CONCLUSIONS: Incomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supra-complete revascularization is associated with improved survival in patients with 3-Vessel CAD, and in single-arterial but not multi-arterial CABG.

Old World Leishmaniasis: an ancient disease with nonstandardized microscopic and clinical classifications.

BACKGROUND: Microscopic and clinical classifications of cutaneous leishmania have been set in the 1980s. Since then, they have been used invariably. Lebanon, a nonendemic country, is suffering from a leishmaniasis epidemic because of the massive population influx from endemic Syria. DESIGN: Patients diagnosed and speciated with leishmania (n = 169) using molecular and microscopic analysis were studied. General demographic data, microscopic data [Ridley's pattern (RP), microscopic pattern, Parasitic Index (PI)] and clinical stage were documented. Clinical score was scored as: 1: inflammatory; 2: proliferative/reorganization; 3: healed phases. The three patterns were studied in comparison to the lesion age and PI. RESULTS: At low PI, the clinical score and microscopic pattern showed healing scores (scores 3 and 4, respectively). In contrast, RP showed variable distribution at low PI. The same pattern is noted when correlating the different patterns with high PI. In comparison to lesion age, none of the three patterns showed the predicted linear correlation with lesion progression. CONCLUSION: In the studied population, the previously adopted classifications did not correlate with the disease progression. Such findings may raise the possibility of evolving disease. The proposed clinical and microscopic patterns showed better correlation with the disease progression.

Head and neck cutaneous leishmania: clinical characteristics, microscopic features and molecular analysis in a cohort of 168 cases.

Lebanon, an underendemic area for cutaneous leishmania (CL), is suffering from a CL outbreak brought by the massive population influx from endemic Syria. CL affects mainly exposed areas; therefore, the head and neck (HN) region is highly susceptible. Individuals diagnosed and speciated with CL (n = 168) using molecular and microscopic analysis on punch biopsy/scrapings were studied. Clinical data, parasitic index (PI) and Ridley's Pattern (RP) were recorded. The HN was divided into 11 anatomic locations. Of 168 patients, 96 patients (57.1 %) had HN involvement and 72 (42.9 %) had no HN involvement. Lesions from the HN were significantly more common in younger patients and were more prone for ulceration, had larger size, higher PI and more advanced RP (p < 0.05). There was no difference in the anatomic distribution of lesions among age groups and genders in the HN group. The cheek area was the most HN involved location. Lesions were less commonly encountered in the veiled area in women. In the community we studied, HN is commonly involved by CL. Lesions with HN involvement were encountered more in pediatric age group and showed more extensive features.

Ongoing epidemic of cutaneous leishmaniasis among Syrian refugees, Lebanon.

In September 2012, a cutaneous leishmaniasis outbreak began among Syrian refugees in Lebanon. For 948 patients in whom leishmaniasis was not confirmed, we obtained samples for microscopic confirmation and molecular speciation. We identified Leishmania tropica in 85% and L. major in 15% of patients. After 3 months of megulamine antimonite therapy, patients initial cure rate was 82%.

The effect of acute kidney injury and discharge creatinine level on mortality following cardiac surgery*.

OBJECTIVES: Acute kidney injury after cardiac surgery is associated with increased operative and late mortality. The objective was to determine if short and long term mortality are systematically improved with completeness of postoperative acute kidney injury reversal or with amount of residual renal function. DESIGN: Retrospective, single center study. SETTING: Tertiary care hospital. PATIENTS: One thousand five hundred and forty-three cardiac surgery patients divided into acute kidney injury groups based on Kidney Disease International Group Outcome criteria. MEASUREMENTS AND MAIN RESULTS: Operative mortality was 3.1% overall and was progressively worse with increasing acute kidney injury: none (0.8%), minimal (1.6%), Kidney Disease International Group Outcome stage 1 (4.3%), stage 2 (17%), and stage 3 (29%). Similar to the operative outcomes, late outcomes were progressively worse with rising amounts of acute kidney injury. The risk of late death was related to amount of acute kidney injury and remaining renal function at discharge. CONCLUSIONS: Acute kidney injury was associated with higher operative and late mortality. Lesser amounts of residual renal function were associated with increased late mortality.

Prediction of celiac disease at endoscopy.

BACKGROUND AND STUDY AIMS: Celiac disease is increasingly recognized worldwide, but guidelines on how to detect the condition and diagnose patients are unclear. In this study the prevalence and predictors of celiac disease were prospectively determined in a cross-sectional sample of Lebanese patients undergoing esophagogastroduodenoscopy (EGD). PATIENTS AND METHODS: Consecutive consenting patients (n = 999) undergoing EGD answered a questionnaire and had blood taken for serologic testing. Endoscopic markers for celiac disease were documented and duodenal biopsies were obtained. The diagnosis of celiac disease was based on abnormal duodenal histology and positive serology. Risk factors were used to classify patients to either high or low risk for celiac disease. Independent predictors of celiac disease were derived via multivariate logistic regression. RESULTS: Villous atrophy (Marsh 3) and celiac disease were present in 1.8 % and 1.5 % of patients, respectively. Most were missed on clinical and endoscopic grounds. The sensitivity of tissue transglutaminase (tTG) testing for the diagnosis of villous atrophy and celiac disease was 72.2 % and 86.7 %, respectively. The positive predictive value of the deamidated gliadin peptide (DGP) test was 34.2 % and that of a strongly positive tTG was 80 %. While the strongest predictor of celiac disease was a positive tTG (odds ratio [OR] 131.7, 95 % confidence interval [CI] 29.0 - 598.6), endoscopic features of villous atrophy (OR 64.8, 95 %CI 10.7 - 391.3), history of eczema (OR 4.6, 95 %CI 0.8 - 28.8), anemia (OR 6.7, 95 %CI 1.2 - 38.4), and being Shiite (OR 5.4, 95 %CI 1.1 - 26.6) significantly predicted celiac disease. A strategy of biopsying the duodenum based on independent predictors had a sensitivity of 93 % - 100 % for the diagnosis of celiac disease, with an acceptable (22 % - 26 %) rate of performing unnecessary biopsies. A strategy that excluded pre-EGD serology produced a sensitivity of 93 % - 94 % and an unnecessary biopsy rate of 52 %. CONCLUSION: An approach based solely on standard clinical suspicion and endoscopic findings is associated with a significant miss rate for celiac disease. A strategy to biopsy based on the derived celiac disease prediction models using easily obtained information prior to or during endoscopy, maximized the diagnosis while minimizing unnecessary biopsies.

Comparing BRAF mutation status in matched primary and metastatic cutaneous melanomas: implications on optimized targeted therapy.

BACKGROUND: Selective BRAF inhibitors have shown dramatic results with regard to improving outcome in patients with melanoma. Testing the BRAF status in matched primary and metastatic melanomas to optimize individual targeted therapy is not well investigated. METHODS: Extended BRAF testing using PCR for 9 mutations and VE1 immunohistochemistry for BRAF V600E detection on 95 lesions including 40 primary melanomas with their matched metastases (n = 42), recurrences (n = 9) and second primaries (n = 4) was performed. Nine patients had multiple metastases. RESULTS: V600E was the only identified mutation type; 35.4% of primary vs. 18.9% of metastatic melanomas. The overall primary-metastatic BRAF status discordance rate was 32.3% using PCR and 27.5% with immunohistochemistry, and was significantly more frequent in primary lesions with mutant BRAF (67%). Males and patients with metastasis to lymph nodes were less likely to be discordant compared to females and those with metastasis to other sites (p = 0.023). Discordant BRAF mutation status was predicted by multivariate binary logistic regression: the presence of a mutant BRAF in the primary melanoma [OR (95% C.I.) = 23.4 (2.4-229.7)] and female gender [OR = 10.6 (1.08-95)]. Inter-metastases BRAF concordance was 100% (6 comparisons). CONCLUSION: A high discordant rate implies the need for clinical trials addressing the response to targeted therapy in patients with discordant BRAF statuses between their primary and metastatic lesions.

Improved accuracy of anticoagulant dose prediction using a pharmacogenetic and artificial neural network-based method.

BACKGROUND: The unpredictability of acenocoumarol dose needed to achieve target blood thinning level remains a challenge. We aimed to apply and compare a pharmacogenetic least-squares model (LSM) and artificial neural network (ANN) models for predictions of acenocoumarol dosing. METHODS: LSM and ANN models were used to analyze previously collected data on 174 participants (mean age: 67.45 SD 13.49 years) on acenocoumarol maintenance therapy. The models were based on demographics, lifestyle habits, concomitant diseases, medication intake, target INR, and genotyping results for CYP2C9 and VKORC1. LSM versus ANN performance comparisons were done by two methods: by randomly splitting the data as 50 % derivation and 50 % validation cohort followed by a bootstrap of 200 iterations, and by a 10-fold leave-one-out cross-validation technique. RESULTS: The ANN-based pharmacogenetic model provided higher accuracy and larger R value than all other LSM-based models. The accuracy percentage improvement ranged between 5 % and 24 % for the derivation cohort and between 12 % and 25 % for the validation cohort. The increase in R value ranged between 6 % and 31 % for the derivation cohort and between 2 % and 31 % for the validation cohort. ANN increased the percentage of accurately dosed subjects (mean absolute error ≤1 mg/week) by 14.1 %, reduced the percentage of mis-dosed subjects (mean absolute error 2-3 mg/week) by 7.04 %, and reduced the percentage of grossly mis-dosed subjects (mean absolute error ≥4 mg/week) by 24 %. CONCLUSIONS: ANN-based pharmacogenetic guidance of acenocoumarol dosing reduces the error in dosing to achieve target INR. These results need to be ascertained in a prospective study.

Low-density lipoprotein levels and not mutation status predict intima-media thickness in familial hypercholesterolemia.

BACKGROUND: Intima-media thickness (IMT) is a well-described marker of cardiovascular disease. In this study we aim to determine whether low-density lipoprotein (LDL) levels and disease-related mutation status can predict IMT in patients with severe familial hypercholesterolemia (FH) referred for or on LDL apheresis. METHODS: Genetic screening, lipid profile testing, and IMT measurements were performed on a series of 33 severe FH patients (19 homozygous) on LDL apheresis treatments (LDL 447 ± 151 mg/dL, age range 6-60 years). Data were then compared with literature IMT-LDL data for normal subjects, mild FH patients, and severe FH patients (18, 41, and 6 studies, respectively). RESULTS: Age-adjusted IMT was linearly related to LDL levels over a wide range of values (<500 mg/dL), except for the severe FH no-apheresis cohort. Alternatively, our severe FH population (mostly on apheresis) did follow the mild FH/control age-adjusted IMT-LDL relation. CONCLUSIONS: In severe FH, measuring LDL levels is more predictive of increased IMT than genetic screening.