Clinical and Translational Science Research Retreat

CD81/CD9 tetraspanins aid plasmacytoid dendritic cells in recognition of HCV-infected cells and induction of IFNα

Shuye Zhang et al. — Tue, 22 May 2012 16:30:00 PDT

Recognition of hepatitis C virus (HCV)-infected hepatocyes and interferon (IFN) induction are critical in antiviral immune response. We hypothesized that cell-cell contact between pDCs and HCV-infected cells was required for IFNα induction via involvement of cell surface molecules. Co-culture of human peripheral blood mononuclear cells (PBMCs) with genotype 1a full length HCV genomic replicon cells (FL) or genotype 2a JFH-1 virus infected hepatoma cells (JFH-1), not with uninfected hepatoma cells (Huh7.5), induced IFNα production. Depletion of pDCs from PBMCs attenuated IFNα release and purified pDCs produced high levels of IFNα after co-culture with FL replicons or JFH-1 infected cells. IFNα induction by HCV-containing hepatoma cells required viral replication, direct cell-cell contact with pDCs, and receptor-mediated endocytosis. We determined that the tetraspanin proteins, CD81 and CD9 and not other HCV entry receptors were required for IFNα induction in pDCs by HCV infected hepatoma cells. Disruption of cholesterol-rich membrane microdomains, the localization site of CD81 or inhibition of CD81 downstream molecule, Rac GTPase, inhibited IFNα production from co-cultures. IFNα production by HCV infected hepatoma cells was decreased in pDCs from HCV infected patients compared to normal controls. We found that pre-exposure of normal PBMCs to HCV viral particles attenuated IFNα induction by HCV infected hepatoma cells or TLR ligands and this inhibitory effect could be prevented by an anti-HCV E2 blocking antibody. In conclusion, our novel data show that recognition of HCV-infected hepatoma cells by pDCs involves CD81/CD9-associated membrane microdomains and induces potent IFNα production.

Endemic Gallbladder Cancer: Is There a Role for Prophylactic Cholecystectomy?

Elan R. Witkowski et al. — Tue, 22 May 2012 16:30:00 PDT

Background: Gallbladder cancer (GBC) is an often lethal malignancy with variable distribution. Incidence in the United States is low. However, in areas of Central/South America, Central Europe, Japan, and the Indian subcontinent, GBC is a major cause of cancer death. Cholecystectomy is safe and commonly performed worldwide. Thus, prophylactic cholecystectomy (PCCY) has been proposed in regions with endemic GBC. We developed a simple decision model to assist caregivers in determining the optimal strategy for managing GBC based on local incidence and technological capabilities.

Methods: Rates of disease and outcomes were derived from a review of the literature. Using TreeAge-Pro software, a decision model was created to simulate expected health outcomes for populations with high GBC incidence, following 3 treatment strategies: no early intervention, one-time screening ultrasound (US), or PCCY. Lifetime cancer-specific survival was the outcome of interest. Sensitivity analyses were performed to determine threshold values.

Results: Based on our model, populations where lifetime risk of GBC exceeds 0.4% may benefit from early intervention by US or PCCY. Two-way sensitivity analysis shows that over a relatively narrow range of disease incidence, US may be favored if sensitivity exceeds 50%. In many cases where lifetime risk exceeds 1%, PCCY may improve survival.

Conclusions: GBC varies in incidence, but affects many individuals in some populations in the Americas. The lethality of GBC may justify aggressive public health intervention including screening or prophylactic cholecystectomy. Decision analysis models using best-available evidence may help determine the optimal treatment of individuals at risk for GBC.

Biodegradable Wound Dressing for Skin Regeneration

Scott E. Wharram et al. — Tue, 22 May 2012 16:30:00 PDT

Using the delayed healing model of diabetic (db/db) mice, we evaluated the ability of a novel silk based dressing to facilitate healing of full-thickness excisional wounds. Silk protein from Bombyx mori was used to create wound dressings via a proprietary electrospinning technique. The resulting dressing is vapor and air transmissible. Eight millimeter diameter full-thickness wounds were created on the backs of diabetic mice and covered with either a standard (n=12) telfa-gauze or the silk (n=12) dressing. At 2 day intervals, the telfa dressings were removed, the wounds photographed, measured and fresh dressings placed. For mice receiving the silk dressing, it was allowed to remain in place unless it became dislodged. In that case, a fresh dressing was placed into the wound bed. Wound healing was followed for 21 days at which time the mice were sacrificed, the wound areas excised and subjected to H & E and Trichrome staining. Wounds covered with the silk dressings developed an eschar encompassing the silk whereas wounds dressed with gauze remained moist and without eschar throughout the study period. Upon histologic examination, 1 of the gauze dressed wounds developed a complete epithelial layer across the wound. The remaining 11 wounds had large areas remaining without an epithelial cover. In contrast, 5 of 12 mice receiving the silk dressing developed complete epithelial layers, 2 additional mice had very small areas remaining without a complete epithelium. The remaining 5 had modest areas without an epithelial covering. The ability of silk dressings to permit the formation of an eschar versus gauze in which the wounds remained wet may contribute significantly to the healing response observed. These results suggest that the breathable, vapor transmissible nature of the silk dressing may be an effective dressing for difficult to heal wounds such as diabetic foot ulcers.

Development of Lateral Flow Fluorescence Assay for the Detection of Trypanosoma

Yuhong Wang et al. — Tue, 22 May 2012 16:30:00 PDT

Trypanosoma such as Trypanosoma brucei and Trypanosoma cruzi, the causative agents for African sleeping sickness and Chagas disease, respectively, have important influence on human health. The methods such as microscopic examination, immunological methods, and molecular methods are used for the identification and detection of Trypanosoma, but none of these methods are ideal to mass screening of samples such as onset of outbreak, epidemiological surveys, and blood unit screening. Therefore, there is a need for an assay which can rapidly, sensitively and specifically detect Trypanosoma.

In this study, Ru(bpy)₃²⁺-doped silica nanoparticles (RuSNP) were used to target nucleic acid sequences in a lateral flow fluorescent assay. This assay was developed to improve the sensitivity and lower the limit of detection as compared to the traditional lateral flow assay. The assay targeted both the spliced leader sequence as well as the polyA tail of the mRNA. The surface of spherical RuSNP was modified by glycidoxypropyl trimethoxysilane (GOPTMS). Amine-terminated oligonucleotides as a bioreceptor were immobilized onto the RuSNP via the interaction between the NH₂ and the epoxy group of the GOPTMS. The conjugate complexes formed were immobilized on the conjugate pad, and the capture oligonucleotides used for test and control lines were immobilized on the nitrocellulose membrane. The effects of the amount of RuSNP, GOPTMS, amine-capped oligonucleotides, and capture oligonucleotides on the test line on the performance of the test strips were investigated and optimized. The fluorescence intensity was evaluated by using a fluorescent microplate reader.

The experimental results showed that the nucleic acid sequence-based and RuSNP-labeled lateral flow assay was very sensitive compared with the gold-labeled test strips and the chemiluminescent test strips we developed previously, and that the limit of detection (LOD) of the test strips developed is 0.4 fmol. The LOD can further be reduced about one order of magnitude when dipstick format was used.

Medication Errors in the Home: A Multisite Study of Children with Cancer

Kathleen E. Walsh et al. — Tue, 22 May 2012 16:30:00 PDT

Context: As treatment for many illnesses shifts from the hospital to the home, medications previously managed by nurses are now managed by patients and their families. Oral chemotherapy and other cancer-related medications are commonly administered to children with cancer at home by their parents.

Objective: To describe the types of errors occurring in the home medication management of children with cancer.

Design: In a prospective observational study at three pediatric oncology clinics in the Northeast and Southeast US, patients undergoing chemotherapy and their parents were recruited from 11/2007-4/2011. We reviewed medical records and checked prescription doses. A trained nurse visited the home, reviewed medication bottles and directly observed administration. Two physicians independently made judgments regarding whether an error occurred and its severity. Overall rates of errors were weighted to account for clustering within sites.

Results: For 92 patients, we reviewed 963 medications and observed 242 medication administrations. We found 72 medication errors. Four errors led to significant patient injury. An additional 40 errors had potential for injury: 2 were life-threatening, 13 serious and 25 significant. Error rates varied between study sites (40 -121 errors per 100 patients); the weighted overall rate was 70.2 errors per 100 patients (95%CI: 58.9-81.6). The weighted rate of errors with injury was 3.6 (1.7-5.5) per 100 patients and with potential to injure the patient was 36.3 (29.3-43.3) per 100 patients. Errors occurred most often in medication administration (e.g.: failure to change doses as instructed), prescribing, and labeling (e.g.: 2 wrong frequency). Errors less often involved chemotherapy than other medications. Clinicians were unaware of 82% of the errors in their patients’ homes.

Conclusions: In a multisite study of outpatient pediatric cancer care, medication errors were common. Rates of preventable medication-related injuries in this outpatient population were comparable or higher than that found in studies of hospitalized patients.

Cost Utility of Treatment of Stress Urinary Incontinence

Emily Von Bargen et al. — Tue, 22 May 2012 16:30:00 PDT

Objective: There are many possible treatment options for stress urinary incontinence. We sought to investigate the cost-utility of non-surgical versus surgical treatments.

Study Design: A decision analysis model was created to compare non-surgical and surgical treatment options for healthy women with stress urinary incontinence. Decision paths included conservative management, pelvic floor physical therapy, pelvic floor physical therapy with electrical stimulation, incontinence pessary and surgical treatment with a midurethral sling. A Markov model cohort analysis was performed with a cycle length of one year starting at age 45 with a lifetime horizon. Probabilities, success rates and utilities for health outcomes were obtained from the literature or, when unavailable, by expert opinion. A cost utility analysis was performed using US recommendations from a societal perspective. This includes cost to the patient and the health plan. Cost data was obtained from Medicare reimbursement in 2012 US dollars. Cost and quality adjusted life years were discounted at 3% per year. Sensitivity analysis was performed to test the validity of our model.

Results: Analysis of the model showed that incontinence pessary was the most cost-effective treatment option with a cost of $11,411 for 18.9 quality adjusted life years. At a willingness to pay threshold of $50,000, incontinence pessary remained the most cost-effective treatment option. At a willingness to pay threshold of $60,000, surgery became the most cost-effective treatment option. Pelvic floor physical therapy and pelvic floor physical therapy with electrical stimulation were dominated at any willingness to pay threshold.

Conclusion: This model shows that surgical correction is likely the most cost-effective treatment option for young healthy women with stress urinary incontinence. These results are driven by the high success rate of minimally invasive slings compared to other treatment modalities. More studies are needed to define utility values for heath states experienced by women with stress urinary incontinence. This will enhance our ability to develop more accurate cost-utility models and offer the best treatment for women affected by incontinence.

Do antipsychotic dose reduction trials result in worsening behavior among nursing home residents with dementia: a systematic review of the literature

Jennifer Tjia et al. — Tue, 22 May 2012 16:30:00 PDT

Background: While federal regulations require gradual dose reduction trials of antipsychotics prescribed for behavior management in nursing home (NH) residents with dementia, widespread concern about precipitating behavioral disturbances limits implementation. We conducted a systematic review of clinical trials reducing antipsychotic drug use in NH residents to determine best dose reduction practices and risk of behavior escalation.

Methods: A comprehensive literature search was conducted in MEDLINE, EMBASE, and International Pharmaceutical Abstracts between January 1970 and October 2011 using the terms “antipsychotic agent or neuroleptic agent,” “dementia,” “nursing homes,” and “withdrawal.” One investigator reviewed abstracts for inclusion based on: English-language, human subjects, clinical trial, nursing home site, and ≥5 participants, and reported reduction in medications due to an intervention. We excluded review articles and commentaries and secondary analysis of main trial results. The remaining articles were reviewed by 2 investigators for final inclusion, resulting in 9 articles.

Results: The nine articles meeting inclusion criteria included randomized controlled trials of both typical and atypical antipsychotics. Study populations ranged in size from 55 to 183 NH residents with dementia and typically targeted patients who were not psychotic and did not have a history of violent behavior. Gradual dose reduction protocols typically followed a strategy of 50% dose reduction per week for 2-3 sequential weeks. Outcomes measured included behavioral problems, cognitive function, and resumption of antipsychotic medications. All 9 studies reported that the majority of residents randomized to gradual dose reductions of antipsychotics had no overall detrimental effect on functional and cognitive status, or exacerbation of behavioral symptoms.

Conclusions: Clinical trials evaluating the withdrawal of antipsychotic medications from NH residents with dementia do not show evidence of rebound behavioral escalation after gradual dose reductions.

Not Just Full of Hot Air: Hyperbaric Oxygen Therapy Increases Survival in Cases of Necrotizing Soft Tissue Infections

Joshua L. Shaw et al. — Tue, 22 May 2012 16:30:00 PDT

INTRODUCTION: The utility of hyperbaric oxygen therapy (HBOT) in the treatment for necrotizing soft tissue infections (NSTI) has not been proven. Previous studies have been subject to significant selection bias since HBOT is not universally available at all medical centers and there is often considerable delay associated with its initiation. We examined the utility of HBOT for the treatment of NSTI in the modern era by isolating centers that have their own HBOT facilities.

METHODS: We queried all centers in the University Health Consortium (UHC) database from 2008 to 2010 that have their own HBOT facilities (N=14). Cases of NSTI were identified by ICD-9 diagnosis codes, which included Fournier’s gangrene (608.83), necrotizing fascitis (728.86), and gas gangrene (040.0). HBOT treatment status was identified by the presence (HBOT) or absence (CONTROL) of ICD-9 procedure code (93.95). We then risk stratified and matched our cohort by UHC’s validated severity of illness (SOI) score. Comparisons were then made using univariate tests of association and multivariable logistic regression.

RESULTS: There were 1,583 NSTI cases at the 14 HBOT-capable centers. 117 (7%) cases were treated with HBOT. Risk stratified univariate outcomes are summarized in the table. There was no difference between HBOT and CONTROL groups in hospital length of stay (LOS), direct cost, complications, and mortality across the three less severe SOI classes (minor, moderate, and major). However, for extreme SOI the HBOT group had fewer complications (45% vs. 66%; p<0.01) and fewer deaths (4% vs. 23%; <0.01) while there were no differences in LOS and cost. Multivariable analysis identified age (OR 0.55; 95% CI 0.44 – 0.68) and SOI (OR 0.29; 95% CI 0.21 – 0.40) as independent predictors of survival. HBOT increased the odds of surviving the index hospitalization (OR 8.8; CI 95% 4.4 – 20.4).

CONCLUSION: At HBOT capable centers, receiving HBOT was associated with a significant survival benefit. HBOT in conjunction with current practices for the treatment of NSTI can be both a cost effective and life saving therapy.

Acute Care Surgery Patterns in the Current Era: Results of a Qualitative Study

Heena Santry et al. — Tue, 22 May 2012 16:30:00 PDT

Introduction: Since Acute Care Surgery (ACS) was first conceptualized as a specialty a decade ago, ACS teams have been widely adopted. Little is known about the structure and function of these teams.

Methods: We conducted 18 open-ended interviews with ACS leaders (1 interview/center representing geographic [New England, Northeast, Mid-Atlantic, South, West, Midwest] and practice [Public/Charity, Community, University] variations). Two independent reviewers analyzed transcribed interviews using an inductive approach to determine major themes in practice variation (NVivo qualitative analysis software).

Results: All respondents described ACS as a specialty treating "time sensitive surgical disease" including trauma, emergency general surgery (EGS), and surgical critical care (SCC). 11/18 combined trauma and EGS into a single clinical team; 6/18 included elective general surgery. Emergency orthopedics, neurosurgery, and triage for all surgical services were rare (1/18 each). 11/18 had blocked OR time. All had a core group of trauma and SCC surgeons; 8/18 shared EGS due to volume, manpower, or competition for EGS call. Many (12/18) had formal morning signout rounds; few (2/18) had prospective EGS data registries. Streamlined access to EGS, evidence-based EGS protocols, and improved communication were considered strengths of ACS. ACS was described as the "last great surgical service" reinvigorated to provide "timely," cost-effective EGS by experts in "resuscitation and critical care" and to attract "young, talented, eager surgeons" to trauma and SCC; however, there was concern that it might become the "waste basket for everything that happens at inconvenient times."

Conclusion: Despite rapid adoption of ACS, its implementation varies widely. Standardization of scope of practice, continuity of care, and registry development may improve EGS outcomes and allow the specialty to thrive.

Serum sodium values and their association with adverse outcomes in moderate-severe traumatic brain injury (TBI)

Lucia Rivera Lara et al. — Tue, 22 May 2012 16:30:00 PDT

Hypernatremia in neurocritically ill patients has been associated with worse neurological outcomes. There may, however, be a treatment effect from osmotherapy combating herniation and hyponatremia, which in turn may exacerbate brain edema, resulting in iatrogenic sodium repletion. In moderate-severe TBI, serum sodium (sNa) disturbances are common, but their impact on patient outcomes is unknown. In a prospective observational cohort study of 144 consecutive moderate-severe TBI patients admitted to a Level I trauma center (UMASS) over the period 11/2009–11/2011, we examined the association of mean, nadir, and peak sNa and hospital discharge neurological outcome (Glasgow Outcome Scale [GOS]). The mean age of this cohort was 51 years, 70% were men, and the median GCS and injury severity scores were 5 and 32, respectively. Using ordinal regression analysis, controlling for admission variables, length of ICU stay, severity of injury, presence of brain edema on head CT, administered hypertonic saline and mannitol, higher mean (p<0.001), higher peak (p=0.01), and higher nadir (p<0.001) sNa values were significantly associated with worse outcome. Our findings suggest that higher sNa values are associated with worse neurological outcome, independent of treatment effect by osmotherapy.

Is pancreatic cancer palliatable? A national study

Elizaveta Ragulin Coyne et al. — Tue, 22 May 2012 16:30:00 PDT

Background: Pancreatic cancer is frequently diagnosed at advanced stages where potentially curative resection is no longer possible. Palliative procedures can be performed; however, results on a national level are unknown. This study examines pancreatic cancer patients who underwent potentially palliative procedures including gastric bypass, biliary bypass surgery, celiac block, biliary stent, gastrostomy or jejunostomy, and examines post-intervention complications and 30-day mortality.

Methods: SEER-Medicare 1991-2005 was used to identify patients with Stage 3-4 pancreatic cancer. Complication rates were calculated including post-op infection, myocardial infarction, aspiration pneumonia, DVT/PE, pulmonary compromise, gastric bleed, acute renal failure, and reoperation. Kaplan-Meier survival analysis was performed. Finally, Cox proportional hazards modeling was used to control for the effects of age, sex, race, stage, and resection.

Results: Of 22,314 pancreatic cancer patients, 858 (3.9%) patients were Stage 3, and 11,149 (50.0%) stage 4. Post-procedure median survival for all patients is approximately two months, with longest survival for biliary bypass patients (3.2mo, 95% CI(2.9-3.7), and lowest survival for jejunostomy 1.3 mo (1.2-1.5) and gastrostomy 1.5 mo (1.4-1.8). Post-procedure 30-day mortality was highest for gastrostomy patients at 41.5%; followed by jejunostomy (39.1%), celiac plexus block (30.0%), gastric bypass (23.8%), biliary bypass (17.8%), and biliary stent (21.2%). The rate of complications averaged 40%, with highest rate for gastrostomy (47.4%) and gastric bypass (45.3%) and lowest for celiac plexus block (29.3%). Stage 4 disease was an independent predictor of death for patients undergoing five out of six procedures.

Conclusion: We found that morbidity and mortality of palliative procedures in unresectable pancreatic cancer is high, especially in stage 4 patients. Further studies need to be conducted to identify patients who will have sufficient expected post-procedure survival to benefit from these palliative interventions.

Caspase-1-dependent, IL-1ß-mediated alcoholic steatohepatitis is ameliorated by IL-1 receptor antagonist treatment in mice

Jan Petrasek et al. — Tue, 22 May 2012 16:30:00 PDT

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of pro-inflammatory cytokines, including interleukin (IL)-1β. IL-1β, Type-I IL-1 receptor (IL1R1) and IL-1 receptor antagonist (IL-1Ra) are all part of the IL-1 superfamily that play a role in inflammation. IL-1β maturation is dependent on Caspase-1. Using wild-type (WT), Caspase-1-, IL-1R1- and IL-1Ra deficient mice fed with Lieber-DeCarli alcohol or control diet, we have identified that signaling mediated by the active IL-1β was required for development of alcohol-induced steatosis, inflammation and injury. Increased IL-1β was due to upregulation of Caspase-1 activity and inflammatory activation. The pathogenic role of IL-1 signaling in ALD was attributable to the presence of IL-1R1 on liver parenchymal cells. Importantly, in vivo intervention with recombinant IL-1Ra, Anakinra, which blocks IL-1 signaling, significantly attenuated both liver steatosis and inflammation. In primary hepatocytes, physiological doses of IL-1β induced steatosis and upregulated the inflammatory and pro-steatotic chemokine MCP-1. MCP-1, but not IL-1β induced hepatocyte cytotoxicity at concentrations found in ALD.

In conclusion, we demonstrate that Caspase-1-dependent upregulation of IL-1β and signaling mediated by IL-1 is crucial in the pathogenesis of ALD in a cell specific manner. Our findings suggest a potential role of IL-1Ra in the treatment of ALD.

Understanding Health Utilities in Women with Urinary Incontinence

Danielle Patterson et al. — Tue, 22 May 2012 16:30:00 PDT

Objectives: The purpose of this study was to compare the health utility of UI in women as derived from the EQ-5D with the gold standard, the Standard Gamble. The secondary aim of this study was to compare health utility values of affected patients to healthy controls.

Materials and Methods: Clinical diagnosis was categorized as normal, stress, mixed or urge urinary incontinence. Healthy controls were read a scenario for stress or mixed UI. All subjects completed the Sandvik Severity Index (SSI), EQ-5D, and Standard Gamble (SG) conversation.

Results: 50 healthy controls and 119 affected subjects were recruited. The mean utility value for incontinence varied based on method: EQ-5D (0.78 + 0.17) and SG (0.85 + 0.20). There was a significant difference between utility scores derived from SG and EQ-5D (p=0.0004). This significant difference was maintained in the subset of women with SUI: EQ-5D (0.81 + 0.16), SG (0.87 + 0.18), p=0.028; but not in women with MUI or UUI. When comparing healthy controls to women with SUI, there were significant differences in the utility values derived by SG (0.76 + 0.26 vs. 0.87 + 0.18, p=0.07) but not by EQ-5D. When comparing healthy controls to women with MUI, there was also a significant difference in the utility derived by SG (0.92 + 0.10 vs. 0.75 + 0.21, p=0.01) but not by EQ-5D. SSI scores moderately correlated with SG utility values and strongly correlated with EQ-5D utility values. Logistic regression analysis showed that utility values were unaffected by age and menopausal status.

Conclusion: This study suggests that using the EQ-5D to quantify the utility of UI may over-estimate the degree of bother when compared to SG assessment. This is important because the SG process more closely approximates the decision to undergo surgery. Relying on the EQ-5D to assess health utilities in women with UI may not be valid.

Use of the BRFSS Follow-up Surveys to Assess Awareness of the Massachusetts Medicaid Cessation Benefit

Mark Paskowsky et al. — Tue, 22 May 2012 16:30:00 PDT

Background: Conducting a BRFSS follow-up survey is an effective method for evaluating special program initiatives. Massachusetts Tobacco Control Program (MTCP) staff designed a brief telephone questionnaire to measure awareness of a new tobacco cessation benefit for the Medicaid population and to identify barriers to utilization of the benefit.

Methods: A telephone call back was conducted by the Massachusetts Department of Public Health (MDPH) from April 2007 – October 2007, 10-16 months after implementation of the smoking cessation benefit. It consisted of a sample of BRFSS respondents between the ages of 18 and 64 years interviewed between March 2007 and September 2007 who agreed to be called back for a follow-up survey. The data consists mainly of smoking and smoking cessation-related questions, insurance related questions, and questions regarding healthcare utilization.

Results: Sixty-two percent of BRFSS respondents provided consent to participate in the follow-up survey. Of those, forty-three percent responded to the survey. Of the 2,399 follow-up survey completions, 487 were Medicaid members. Survey results show that Medicaid smokers at follow-up had a high awareness of quitline services (64%) and the benefit (32%). Compared to non-Medicaid smokers, more Medicaid smokers reported intentions to use tobacco cessation medication if referred by a health care provider (55% vs. 47%, p=.04).

Conclusions: Using the BRFSS call-back survey approach made it possible to administer the survey to smokers in the Medicaid population without a laborious and expensive process of screening Medicaid eligible smokers from the general population. Thus, the approach is cost-effective and population-based. The results showed high awareness of quitline services and smoking cessation of the Medicaid smoking cessation benefit, and, most importantly, a higher rate of reported intention to use cessation medication among the Medicaid smoking population.

Healthy Food Accessibility in Grocery Stores in Central Massachusetts

Barbara C. Olendzki et al. — Tue, 22 May 2012 16:30:00 PDT

BACKGROUND. Accessibility to healthy food is one of the most influential community-level factors affecting obesity and chronic disease. The Community Nutrition Environment Evaluation Data System (C-NEEDS) is a set of instruments for objectively assessing availability and quality of 61 major healthy and unhealthy food items in foods stores in the Northeast region.

METHODS. The C-NEEDS was developed considering seasonal variations, cultural relevance and utility to cardiovascular health research. Both inter- and intra-rater reliability tests showed a high degree of agreement. Using the instruments, we conducted four rounds of longitudinal surveys of 107 grocery stores in Worcester County, Massachusetts between 2007 and 2010. A healthy food availability index (HFAI, 0-37 points) was calculated for each store, a higher score indicating a greater availability and better quality of healthy foods. Using linear regression models, we examined variations in HFAI in relation to community household income and housing density.

RESULTS. Store-level HFAI did not vary significantly by tertile of community median income, but did vary by housing density. High-density communities (upper tertile) had the greatest percentage of stores in the top HFAI tertile (34-37 points). Middle-density communities had the greatest percentage of stores in the low HFAI tertile (0-17 points). A majority of the stores located in low-density communities had middle range of HFAI (18-33 points). The mean HFAI increased with each successive round of grocery store surveys (β=2.02/round [95% confidence interval 0.74-3.31]).

CONCLUSION. Access to healthy foods improved slightly over time, however, notable disparities still existed in Central Massachusetts during the study period. Better access was associated with community housing density but not median household income. Further studies on the causes of the disparities may inform public health organizations about necessary community actions to reduce these disparities.

Racial and Socioeconomic Disparities in Biological and Perceived Chronic Stress: Does Group Identification Matter?

Kymberlee M. O'Brien et al. — Tue, 22 May 2012 16:30:00 PDT

Objective: Hair cortisol has been recently identified as a biological index of stress via long-term alterations in HPA activity, although population norms and relationships to perceived stress measures have not yet been established.

In the present study, 135 adults (ages 18-66; M = 30.26, SD = 12.80; 87 females) from the diverse UMass Boston campus participated in a study assessing chronic stress (via hair cortisol), perceived stress (via self-reported indices), and health indictors (WHR and blood pressure). Since hair grows on average 1cm per month, we captured approximately 3 months of retrospective cortisol levels.

Results: Hair cortisol was uncorrelated with subjective stress indices, unless collapsed into a composite across several domains. Differences in objective and subjective stress measures were found for sociodemographic factors including racial/ethnic identity, sex, and SES. Specifically, highest hair cortisol levels were found by gender (males were higher) and race (minorities were higher), whereas subjective stress was positively associated with race (minorities were higher), and negatively associated with SES and age. Subjective stress was not significantly different by gender.

Examining interactions of predictors, results obtain that Race by SES predicted hair cortisol, perceived stress, well-being, and health indicators but in unexpected directions. Minorities in high SES had the greatest hair cortisol, subjective stress, systolic blood pressure, waist cm, and lower reported well-being, compared to the non-minority high SES group

The unexpected findings of deleterious outcomes for high SES minorities suggest the necessity of further studies examining social identity, the prevalence of discrimination in high SES, and potential protective factors.

Moreover, these findings give evidence that hair cortisol, as a biomarker of long-term HPA activity, may not always be correlated with perceptions of stress across specific domains, but rather may provide a broad non-specific assessment of chronic stress, where objective and subjective indices may be uncoupled.

Impact of medical and neurological ICU complications on moderate-severe traumatic brain injury (TBI)

Susanne Muehlschlegel et al. — Tue, 22 May 2012 16:30:00 PDT

Certain admission characteristics are known predictors of adverse outcomes in patients with moderate-severe TBI, but explain only 1/3 of outcome variability. Intensive care unit (ICU) complications occur frequently in this population, but their impact on patient outcomes remains poorly defined. In a prospective observational cohort study of 170 consecutive moderate-severe TBI patients admitted to Level I trauma center (UMASS) over the period 11/2009–2/2012, we examined the association of ICU complications and 3-month outcome (Glasgow Outcome Scale [GOS]). The mean age was 51 years, 72% were men, and the median GCS and injury severity scores were 4 and 29, respectively. Using multiple logistic regression analysis, hypotension requiring vasopressors (HRV) was the strongest predictor of poor outcome (GOS 1-3 [OR 2.8; 95% CI 1-7.5]) among medical complications. After combining medical with neurological ICU complications, brain herniation (OR 5.8; 95% CI 1.1-30.2) and intracranial rebleeding (OR 2.9; 95% CI 1-8.4) were the strongest predictors of poor outcome, while HRV approached significance (OR 2.4; 95% CI 0.9-6.4). We identified important potentially modifiable predictors of adverse outcomes after moderate-severe TBI. Confirmation of our findings in a larger cohort is warranted.

Incidence rates of ICU complications in moderate-severe traumatic brain injury (TBI)

Susanne Muehlschlegel et al. — Tue, 22 May 2012 16:30:00 PDT

Retrospective studies suggest that non-neurologic organ failure may contribute to 2/3 of all deaths after TBI, but the actual incidence rates of specific intensive care unit (ICU) complications in moderate-severe TBI are not known. In a prospective observational cohort study of consecutive TBI patients from a single Level I trauma center (UMASS) over the period 11/2009 – 2/2012, we identified the ten most common medical complications after ICU admission according to strict pre-specified criteria in 170 moderate-severe TBI patients. The mean age of the study sample was 51 years, 72% were men, and the median GCS and injury severity scores were 4 and 29, respectively. Incidence rates of the ten most common medical complications in the ICU were: hyperglycemia (75%), fever (62%), systemic inflammatory response syndrome (38%), cardiac complications (36%), hypotension requiring vasopressors (35%), pneumonia (any type [34%]); sepsis (33%), anemia requiring transfusion (31%), other pulmonary complications (ARDS, pulmonary edema [26%]), and hyponatremia (sodium ≤134mEq/L; [23%]). Medical complications in moderate-severe TBI are very common, and their association with important patient outcomes should be further investigated. Specific medical complications may pose attractive modifiable treatment targets to improve the outcome of moderate-severe TBI patients.

Use of whole plant Artemisia annua L. as an antimalarial therapy

Elfawal Mostafa et al. — Tue, 22 May 2012 16:30:00 PDT

Anti-malarial drugs are primary weapons for reducing Plasmodium transmission in human populations. Successful drugs have been highly efficacious and inexpensive to synthetically manufacture. Emergence of resistant parasites reduces the lifespan of each drug that is developed and deployed. Currently, the most effective anti-malarial is artemisinin (AN), which is extracted from the leaves of Artemisia annua. Because of its poor pharmacokinetic properties and prudent efforts to curtail emergence of resistance, AN is prescribed only in combination with other anti-malarials composing an Artemisinin Combination Therapy (ACT). Low yield in the plant and the added cost of secondary anti-malarials in the ACT, make AN in the developing world a costly treatment. Here we show that dried leaves of A. annua administered orally are more effective at killing malaria parasites than a comparable dose of purified drug in a rodent malaria model (P. chabaudi). A single dose of whole plant (WP) A. annua containing 24 mg/kg AN clears 99% of parasites, where a comparable dose of pure drug has half that effect. This is consistent with findings that blood levels of AN are 40 times greater in mice receiving WP versus those given pure drug. We hypothesize that in addition to increasing bioavailability of AN, administration of WP alone may constitute a combination therapy because it contains other anti-malarial compounds that have been shown to synergize with AN. Inexpensive, efficacious, and resilient treatment for malaria based upon WP A. annua that can be grown and processed locally would be an effective addition to the global effort to reduce malaria morbidity and mortality.

Mid-gestation Angiogenic Biomarker Levels are Increased in Women at High Risk for Preeclampsia

Tiffany A. Moore Simas et al. — Tue, 22 May 2012 16:30:00 PDT

Background: Pre-pregnancy hypertension and diabetes mellitus, multiple gestations, prior preeclampsia, are significant risk factors for preeclampsia. Whether altered maternal levels of angiogenic factors contribute to increased preeclampsia risk in these conditions is unknown. Our objective was to compare maternal serum angiogenic biomarker levels in women with major risk factors for preeclampsia and healthy controls.

Methods: Women presenting for prenatal care were enrolled if they had one of the following preeclampsia risk factors: pre-pregnancy hypertension and/or diabetes mellitus, nulliparity with pre-pregnancy BMI>30, multiple gestations, or prior preeclampsia. Healthy control pregnancies without these risk factors were enrolled for comparison. Maternal serum samples were collected at 3 pre-specified gestational windows between 23 and 36 weeks gestation. sFlt1, sEng, and PlGF were measured by ELISA. The (sFlt1+sEng):PlGF ratio was calculated and compared for each risk group at each gestational window.

Results: Gestational patterns of angiogenic biomarkers differed in high-risk groups vs. healthy control subjects. The angiogenic ratio (sFlt1+sEng):PlGF was higher for all high risk groups except obesity/nulliparity as compared with healthy control subjects after 28 weeks gestation. Biomarker ratio levels were highest in subjects with MG and prior PE, and differences from the health control group became more pronounced as gestation progressed. Women with hypertension/diabetes had more subtle differences as compared with healthy control subjects.

Conclusion: Women with preeclampsia risk factors had higher angiogenic ratios compared with healthy control women. This study illuminates the interplay between risk factors and placental angiogenic biomarkers in the pathogenesis of preeclampsia.