Alpha-Gal Syndrome and Cardiac Surgery.

Galactose-alpha-1,3-galactose (alpha-gal) is a carbohydrate expressed by all mammals except for humans and certain old-world primates. It can be found in a plethora of products derived from mammals, including milk, organs, skeletal muscle and gelatin, in addition to products prepared with mammalian cells or constituents. In the late 2000s, an association between tick bites and the development of immunoglobulin E antibodies to the alpha-gal carbohydrate was discovered. The term "alpha-gal syndrome" (AGS) was then coined to describe allergic reactions to mammalian meat or other alpha-gal-containing products derived from mammals. Symptoms are often delayed several hours from consumption and can be urticarial and/or gastrointestinal. Medications and bioprosthetic inserts derived from mammals were also noted to cause allergic reactions in affected patients. Cardiac surgery, in particular, is considered high risk, given that unfractionated heparin has a bovine or porcine origin and is administered in large doses for cardiopulmonary bypass. Bioprosthetic valves have similar origins and risks. Awareness of AGS in cardiac surgery patients can lead to decreased risk preoperatively and inform management perioperatively and postoperatively. In this narrative review, we have reviewed the published literature relevant to AGS in patients undergoing cardiac surgery and shared our treatment approach.

ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients.

Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for the SARS-CoV-2 spike protein receptor-binding domain (RBD) is angiotensin-converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have a negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity-ACE2-like abzymes. To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn2+ for activity. However, we found that the plasma from some patients studied could specifically cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium EDTA anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn2+ was added or the plasma was diluted to decrease EDTA concentration. After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis. IMPORTANCE: We provide what we believe to be the first description of angiotensin-converting enzyme 2 (ACE2)-like enzymatic activity associated with immunoglobulin in COVID-19 patients. COVID-19 includes many puzzling clinical features that have unclear pathogenesis, including a hyperinflammatory state, abnormalities of the clotting cascade, and blood pressure instability. We hypothesized that some patients with COVID-19 patients may produce antibodies against SARS-CoV-2 with enzymatic activity, or abzymes, that target important proteolytic regulatory cascades. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds ACE2 on the surface of the future host cell. This means that the RBD has a negative molecular image of ACE2. We hypothesized that some antibodies produced against the RBD would have, in turn, a negative molecular image of the RBD sufficiently similar to ACE2 to have ACE2-like catalytic activity. In other words, some anti-RBD antibodies would be ACE2-like abzymes. Abzymes elicited by SARS-CoV-2 infection have the potential to affect host physiology.

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

IgE to common food allergens is associated with cardiovascular mortality in the National Health and Examination Survey and the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: In individuals without symptomatic food allergy, food-specific IgE is considered clinically irrelevant. However, recent studies have suggested that galactose-α-1,3-galactose (alpha-gal) IgE is associated with cardiovascular (CV) disease. OBJECTIVE: We sought to determine whether sensitization to common food allergens is associated with CV mortality. METHODS: The association between IgE sensitization to foods and CV mortality ascertained to 2019 was examined in the National Health and Examination Survey (NHANES) 2005-2006 and the Wake Forest site of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort; MESA enrolled adults without baseline clinical CV diseases between 2000 and 2002. Total and specific IgE was measured to cow's milk, egg, peanut, shrimp, and a panel of aeroallergens (NHANES), and to cow's milk, alpha-gal, peanut, dust mite, and timothy grass (MESA). Cox proportional hazard models were constructed, adjusting for sex, age, race/ethnicity, smoking, education, and asthma. RESULTS: A total of 4414 adults from NHANES (229 CV deaths) and 960 from MESA (56 CV deaths) were included. In NHANES, sensitization to at least 1 food was associated with higher CV mortality (hazard ratio [HR], 1.7 [95% confidence interval (CI), 1.2-2.4], P = .005). Milk sensitization was particularly associated (HR, 2.0 [95% CI, 1.1-3.8], P = .026), a finding replicated in MESA (HR, 3.8 [95% CI, 1.6-9.1], P = .003). Restricting analyses in NHANES to consumers of the relevant allergen strengthened food sensitization relationships, unmasking shrimp and peanut sensitization as additional risk factors for CV mortality. CONCLUSIONS: The finding that food sensitization is associated with increased risk of CV mortality challenges the current paradigm that sensitization without overt allergy is benign. Further research is needed to clarify mechanisms of this association.

Pembrolizumab Induced Acute Persistent Airway Disease in a Patient with Recurrent Respiratory Papillomatosis (RRP).

OBJECTIVE: To present an uncommon but serious, recently identified complication of checkpoint inhibitor therapy in a patient treated with pembrolizumab infusion for disseminated recurrent respiratory papillomatosis (RRP). METHODS: Case report. RESULTS: A 43-year-old woman with underlying asthma developed acute hypoxic respiratory failure within 24 hours of her third infusion of pembrolizumab for treatment of intractable, disseminated recurrent respiratory papillomatosis. Pulmonary function testing revealed a severe intra-thoracic obstructive ventilatory defect. Discontinuation of pembrolizumab, ventilatory support, and treatment with systemic and inhaled corticosteroids resulted in resolution of respiratory failure; however, her underlying asthma remains poorly controlled. CONCLUSION: To our knowledge, this case is the first report of pembrolizumab-induced obstructive respiratory failure in a patient being treated for RRP.

Percutaneous Closure of a Cribriform Secundum Atrial Septal Defect and Patent Foramen Ovale.

Atrial septal defects (ASDs) and patent foramen ovale (PFO) are common congenital cardiac malformations that portend a higher risk of ischemic stroke. Percutaneous closure of ASDs using septal occluder devices has proven to be a safe and effective alternative to surgery. We present a case of symptomatic cribriform secundum ASD and PFO who underwent successful percutaneous closure using two Amplatzer occluder devices using a novel "sandwich technique."

Optimal umbilical cord blood collection, processing and cryopreservation methods for sustained public cord blood banking.

BACKGROUND AIMS: Umbilical cord blood is an established source of stem cells in patients with hematologic malignancies who do not have HLA-compatible matched related or unrelated donors. The success of an umbilical cord blood transplant depends on the dose of total nucleated and CD34+ cells infused. Therefore, collecting, banking and listing high-quality cord blood units with high total nucleated and CD34+ cell dose are essential. METHODS: Here the authors describe their cord blood bank's novel collection technique, which involves both in utero and ex utero collection of a single cord blood unit. The authors also evaluated maternal, neonatal and collection parameters that may impact the cell dose. RESULTS: Maternal gestational age and race, and neonatal weight and sex correlated with the total nucleated cell dose. CONCLUSIONS: The optimized collection of umbilical cord blood is critical for its use as a source of stem cells for transplantation.

Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD.

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.

Safety of Intravenous Heparin for Cardiac Surgery in Patients With Alpha-Gal Syndrome.

BACKGROUND: Alpha-gal syndrome is a tick-acquired disease caused by immunoglobulin E (IgE) to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), causing allergic reactions to meat and products sourced from nonprimate mammals. As heparin is porcine-derived, we hypothesized that patients with alpha-gal syndrome who received high-dose heparin for cardiac surgery would have increased risk of anaphylaxis. METHODS: All cardiac surgery patients at an academic medical center from 2007 to 2019 were cross-referenced with research and clinical databases for the alpha-gal IgE blood test. Clinical data were obtained through the institutional Society of Thoracic Surgeons Adult Cardiac Database and chart review. Patients were stratified by development of an allergic reaction for univariate statistical analysis. RESULTS: Of the 8819 patients, 17 (0.19%) had a positive alpha-gal test before cardiac surgery. Of these 17 patients, 4 (24%) had a severe allergic reaction. The median alpha-gal titer was significantly higher in patients with a reaction (75 [interquartile range, 61-96] IU/mL vs 8 [interquartile range, 3-18] IU/mL; P = .006). There were no differences in median heparin loading dose, total dose, or maximum activated clotting time (all P > .05). In a subgroup of 8 patients with recent alpha-gal IgE level, 4 (50%) developed an allergic reaction. CONCLUSIONS: Although alpha-gal is rare in patients undergoing cardiac surgery, there is up to a 50% risk of serious allergic reaction to heparin for cardiopulmonary bypass. Higher preoperative alpha-gal titers may confer a higher risk of severe allergic reaction. For patients with a clinical suspicion of alpha-gal syndrome, we recommend prescreening with IgE levels and premedicating before receiving high doses of intravenous heparin.

A Systematic Review and Meta-analysis of Surgical Treatment of Ectopic Pregnancy with Salpingectomy versus Salpingostomy.

OBJECTIVE: To evaluate the fertility outcomes of salpingectomy compared with those of salpingostomy among patients treated for tubal ectopic pregnancies, including a separate analysis of women with risk factors along with a review of the surgical technique. DATA SOURCES: Systematic review and meta-analysis from 1990 to the present through PubMed, Embase, CINAHL, and Ovid MEDLINE. The search string included "tubal pregnancy" or "ectopic" as well as "salpingectomy" and various terms describing salpingotomy. METHODS OF STUDY SELECTION: Articles studying women who underwent surgical management of an ectopic pregnancy and the contrasted outcomes of salpingectomy vs salpingostomy were reviewed. The primary outcomes included subsequent intrauterine pregnancy (IUP) and repeat ectopic pregnancy (REP). TABULATION, INTEGRATION, AND RESULTS: Two randomized controlled trials (RCTs), which consisted mostly of patients classified as low risk, and patients from 16 cohort studies were included. In the RCTs, there was no significant difference in the odds of subsequent IUP in patients who underwent a salpingectomy compared with those who were treated with salpingotomy (odds ratio [OR] 0.97; 95% confidence interval [CI], 0.71-1.33). However, a significant and clinically meaningful difference was noted in the cohort studies, with the patients having a lower chance of IUP after salpingectomy (OR 0.45; 95% CI, 0.39-0.52). No significant difference was noted in the OR for a REP in the randomized trials (OR 0.77; 95% CI, 0.41-1.47), but the patients followed in the cohort studies had a cumulatively higher risk of REP after a salpingostomy (OR 0.73; 95% CI, 0.60-0.90). The subgroup analysis examining women within the studies with risk factors for tubal pathology found an even more impressive lowering in the odds of a subsequent IUP in patients classified as at-risk who were treated with salpingectomy (OR 0.30; 95% CI, 0.17-0.54), with a change in the direction of the odds for an REP rate favoring those who were treated with salpingostomy (OR 1.96; 95% CI, 0.88-4.35). CONCLUSION: Salpingectomy has clear advantages over salpingostomy, and RCTs consisting mainly of patients classified as low risk show no difference in outcomes between salpingectomy and salpingostomy. However, in cohort studies inclusive of all patients, the likelihood of a subsequent spontaneous IUP is decreased in patients treated with salpingectomy, and salpingostomies may be especially underused in women with risk factors for tubal disease.

Surgical morbidity of transsylvian versus transcortical approaches to insular gliomas.

OBJECTIVE: The choice of transsylvian versus transcortical corridors for resection of insular gliomas remains controversial. Functional pathway compromise from transcortical transgression and vascular injury during transsylvian dissection are the primary concerns. In this study, data from a single-center experience with both approaches were compared to determine whether one approach was associated with a higher rate of morbidity than the other. METHODS: The authors identified 100 consecutive patients who underwent resection of pure insular gliomas at the Barrow Neurological Institute. Volumetric analysis was performed using FLAIR and contrast-enhanced T1-weighted MRI for low- and high-grade gliomas, respectively, for extent of resection (EOR) and diffusion-weighted sequences were used to detect for postoperative ischemia. Step-wise logistic regression analysis was performed to identify predictors of neurological morbidity. RESULTS: Data from 100 patients with low-grade or high-grade insular gliomas were analyzed. Fifty-two patients (52%) underwent a transsylvian approach, and 48 patients (48%) underwent a transcortical approach. The mean (± SD) EOR was 91.6% ± 12.4% in the transsylvian group and 88.6% ± 14.2% in the transcortical group (p = 0.26). Clinical outcome metrics for the 2 groups were similar. Overall, 13 patients (25%) in the transsylvian group and 10 patients (21%) in the transcortical group had evidence of ischemia on postoperative MR images. For both approaches, high-grade histology was associated with permanent morbidity (p = 0.01). For patients with gliomas located within the superior-posterior quadrant of the insula, development of postoperative ischemia was associated with only the transsylvian approach (46% vs 0%, p = 0.02). CONCLUSIONS: Areas of restricted diffusion are common on postoperative MRI following resection of insular gliomas, but only a minority of these patients develop permanent neurological deficits. Insular glioma patients with high-grade histology may be at particular risk for developing symptomatic postoperative ischemia. Both the transcortical and transsylvian corridors are associated with reasonable morbidity profiles, although gliomas situated within the superior-posterior quadrant of the insula are more safely accessed with a transcortical approach.

Association Between Residential Greenness and Cardiovascular Disease Risk.

Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on ß-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity.

Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes.

BACKGROUND: Studies have shown select associations between cardiovascular risk factors and dementia, but mostly focused on Alzheimer's Disease (AD). OBJECTIVE: We enhance these works by evaluating the relationship between the presence of cardiovascular risk factors and the rate of cognitive decline, measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR-SUM) on four common dementia subtypes (AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD), as well as non-demented elderly individuals (normal)). METHOD: We used generalized linear mixed models with random intercepts to account for correlation at the patient and center levels for each dementia subtype adjusting for time since initial visit, baseline cognitive score, age, and demographic factors. The cardiovascular risk factors evaluated included body mass index, diabetes, years of smoking, atrial fibrillation, hypertension, and hypercholesterolemia. RESULTS: Patients diagnosed with AD (n=1899), DLB (n=65), FTD (n=168), or VaD (n=13); or lacked cognitive impairment (normal) (n=3583) were evaluated using data from the National Alzheimer's Coordinating Centers. Cardiovascular risk factors were associated with select dementia subtypes including AD and FTD. Using MMSE and CDR-SUM, recent or active hypertension and hypercholesterolemia were associated with a slower cognitive decline for AD patients, while higher body mass index and years of smoking were associated with a slower cognitive decline for FTD patients. However, several cardiovascular factors demonstrated associations with more rapid cognitive decline. CONCLUSION: These results demonstrate disease specific associations and can provide clinicians guidance on predicted cognitive changes at the group level using information about cardiovascular risk factors.

An extent of resection threshold for seizure freedom in patients with low-grade gliomas.

OBJECTIVE Seizures are the most common presenting symptom of newly diagnosed WHO Grade II gliomas (low-grade glioma [LGG]) and significantly impair quality of life. Although gross-total resection of LGG is associated with better seizure control, it remains unclear whether an extent of resection (EOR) "threshold" exists for long-term seizure control. Specifically, what proportion of FLAIR-positive tissue in patients with newly diagnosed LGG must be removed to achieve Engel Class I seizure freedom? To clarify the EOR threshold for long-term seizure control, the authors analyzed data from a consecutive series of patients with newly diagnosed LGG who presented with seizures and subsequently underwent microsurgical resection. METHODS The authors identified consecutive patients with newly diagnosed LGG who presented with seizures and were treated at the Barrow Neurological Institute between 2002 and 2012. Patients were dichotomized into those who were seizure free postoperatively and those who were not. The EOR was calculated by quantitative comparison of pre- and postoperative MRI. Univariate analysis of these 2 groups included the chi-square test and the Mann-Whitney U-test, and a multivariate logistic regression was constructed to predict the impact of multiple independent variables on the likelihood of postoperative seizure freedom. To determine a threshold of EOR that optimizes seizure freedom, a receiver operating characteristic curve was plotted and the optimal point of discrimination was determined. RESULTS Data from 128 patients were analyzed (male/female ratio 1.37:1; mean age 40.8 years). All 128 patients presented with seizures, usually generalized (n = 57, 44.5%) or simple partial (n = 57, 44.5%). The median EOR was 90.0%. Of 128 patients, 46 (35.9%) had 100% volumetric tumor resection, 64 (50.0%) had 90%-99% volumetric tumor resection, and 11 (8.6%) had 80%-89% volumetric tumor resection. Postoperatively, 105 (82%) patients were seizure free (Engel Class I); 23 (18%) were not (Engel Classes II-IV). The proportion of seizure-free patients increased in proportion to the EOR. Predictive variables included in the regression model were preoperative Karnofsky Performance Scale score, seizure type, time from diagnosis to surgery, preoperative number of antiepileptic drugs, and EOR. Only EOR significantly affected the likelihood of postoperative Engel Class I status (OR 11.5, 95% CI 2.4-55.6; p = 0.002). The receiver operating characteristic curve generated based on Engel Class I status showed a sensitivity of 0.65 and 1 - specificity of 0.175, corresponding to an EOR of 80%. CONCLUSIONS For adult patients with LGG who suffer seizures, the results suggest that seizure freedom can be attained when EOR > 80% is achieved. Improvements in both the proportion of seizure-free patients and the durability of seizure freedom were observed beyond this 80% threshold. Interestingly, this putative EOR seizure-freedom threshold closely approximates that reported for the overall survival benefit in newly diagnosed hemispheric LGGs, suggesting that a minimum level of residual tumor burden is necessary for both disease and symptomatic progression.

Impact of communities, health, and emotional-related factors on smoking use: comparison of joint modeling of mean and dispersion and Bayes' hierarchical models on add health survey.

BACKGROUND: The analysis of correlated binary data is commonly addressed through the use of conditional models with random effects included in the systematic component as opposed to generalized estimating equations (GEE) models that addressed the random component. Since the joint distribution of the observations is usually unknown, the conditional distribution is a natural approach. Our objective was to compare the fit of different binary models for correlated data in Tabaco use. We advocate that the joint modeling of the mean and dispersion may be at times just as adequate. We assessed the ability of these models to account for the intraclass correlation. In so doing, we concentrated on fitting logistic regression models to address smoking behaviors. METHODS: Frequentist and Bayes' hierarchical models were used to predict conditional probabilities, and the joint modeling (GLM and GAM) models were used to predict marginal probabilities. These models were fitted to National Longitudinal Study of Adolescent to Adult Health (Add Health) data for Tabaco use. RESULTS: We found that people were less likely to smoke if they had higher income, high school or higher education and religious. Individuals were more likely to smoke if they had abused drug or alcohol, spent more time on TV and video games, and been arrested. Moreover, individuals who drank alcohol early in life were more likely to be a regular smoker. Children who experienced mistreatment from their parents were more likely to use Tabaco regularly. CONCLUSIONS: The joint modeling of the mean and dispersion models offered a flexible and meaningful method of addressing the intraclass correlation. They do not require one to identify random effects nor distinguish from one level of the hierarchy to the other. Moreover, once one can identify the significant random effects, one can obtain similar results to the random coefficient models. We found that the set of marginal models accounting for extravariation through the additional dispersion submodel produced similar results with regards to inferences and predictions. Moreover, both marginal and conditional models demonstrated similar predictive power.

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial.

INTRODUCTION: To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aß levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. METHODS: This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. RESULTS: A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. CONCLUSION: This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.

The National Incidence and Resource Utilization of Burn Injuries Sustained While Smoking on Home Oxygen Therapy.

Considerable risk of burn injury exists for those patients on home oxygen therapy (HOT) who continue to smoke. In this study, the authors sought to establish the national incidence of burns incurred while smoking on HOT and to determine the resource utilization and sequelae of these injuries. A retrospective review of the American Burn Association's National Burn Repository was conducted to identify patients burned while on HOT during the years 2002 to 2011. Duplicate entries, as well as records of follow-up visits and readmissions, were removed. Univariate analysis was used to compare the differences between patients sustaining burn injuries related to HOT and patients with other mechanisms of injury. Multivariate analysis provided odds ratios for mortality controlling for all significant variables. The frequency of burns sustained on HOT significantly increased during the 10-year period reviewed and were associated with increased comorbidities and certain complications. Compared with non-HOT injuries, HOT injuries had higher incidence of inhalation injury and mortality. Inhalation injury was the strongest predictor of mortality in HOT burn injuries. The likelihood of poor prognosis was even more pronounced in patients who required intubation. Smoking was responsible for 83% of the HOT burn injuries described here. Therefore, smoking cessation counseling and treatment should be mandatory in all patients prescribed HOT.

Factors in Free Fasciocutaneous Flap Complications: A Logistic Regression Analysis.

BACKGROUND: Free tissue transfer using fasciocutaneous flaps has increased in frequency over the past decade. Predictive analyses are lacking for fasciocutaneous free flaps in terms of complication rates for reconstruction. This study therefore was designed to identify key variables that drive complications in fasciocutaneous free flap surgery. METHODS: A retroactive chart review of 91 patients undergoing 91 fasciocutaneous flaps was performed. Twelve variables were identified and tracked through clinic and hospital charts (i.e., surgeon experience, hospital, age, flap type, traumatic wound, smoking, large fasciocutaneous flap, type of anastomosis, recipient vessel choice, sex, anatomical region of wound, and flap debulking). A logistic regression model was used to determine the presence of complications associated with the prescribed predictors. RESULTS: The model revealed that smoking, age, anatomical area of wound, flap size, flap type, and presence of a traumatic wound impacted complications. The model was found to be a good fit (Hosmer-Lemeshow, p = 0.135). Factors impacting complications with fasciocutaneous flaps included anatomical area (62.3 percent increase in complications; p = 0.047), surgeon experience (27 percent reduction in complications; p = 0.007), and reconstruction of a trauma activation patient (80 percent reduction in complications; p = 0.025). CONCLUSION: The implications of these findings can be used to contain cost and minimize poor outcomes within the health care system.