Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial.

Background: Topical anti-inflammatory therapy is a cornerstone of treatment for atopic dermatitis (AD). However, many unmet needs remain with existing therapies. B244 is a live topical biotherapeutic being tested for the reduction of pruritus and improvement of eczema signs in patients with AD. We aimed to assess the safety and efficacy of B244, compared to vehicle, for patients with mild-to-moderate AD and moderate-to-severe pruritus. Methods: In this randomised, placebo-controlled, double-blind phase 2b trial, adults aged 18-65 years with mild-to-moderate AD and moderate-to-severe pruritus were enrolled across 56 sites in the USA. Patients were randomised 1:1:1 into a low-dose (optical density at 600 nm [OD] 5.0), high-dose (OD 20.0), or vehicle group for the 4-week treatment period and a 4 week follow-up period. Patients were instructed to apply the topical spray twice daily throughout the treatment period. Randomisation was centrally based (random alternating blocks of 6 and 3) and stratified by site. All participants, investigators, and those assessing outcomes were blinded to the treatment group assignments. The primary endpoint was the mean change in pruritus as measured by the Worst Itch Numeric Rating Scale (WI-NRS) at 4 weeks. Safety was tracked throughout the study. Primary efficacy analyses included the modified intent-to-treat (mITT) population, encompassing those who received at least one dose of study drug and attended at least one post-baseline visit. The safety population included all participants who received at least one does of study drug. This study is registered with ClinicalTrials.gov, NCT04490109. Findings: Between June 4, 2020 and October 22, 2021, 547 eligible patients were enrolled. All study endpoints were meaningfully improved with B244 compared to vehicle. The WI-NRS score was reduced by 34% (-2.8 B244 vs -2.1 placebo, p = 0.014 and p = 0.015 for OD 20.0 and OD 5.0), from a baseline score of >8. B244 was well tolerated with no serious adverse events (SAEs); treatment-emergent adverse events (TEAEs) and treatment related TEAEs were low in incidence, mild in severity, and transient. 33 (18%) of 180 patients given B244 OD 5.0, 29 (16%) of 180 patients given B244 OD 20.0, and 17 (9%) of 186 patients given placebo reported treatment-emergent adverse events; headache was the most frequent (3%, 2%, and 1%, respectively). Interpretation: B244 was well tolerated and demonstrated improved efficacy compared to vehicle in all primary, secondary, and exploratory endpoints and should be further developed as a novel, natural, fast-acting topical spray treatment option for AD and associated pruritus. Funding: AOBiome Therapeutics.

Nutritional status and body composition in patients with peripheral arterial disease: A cross-sectional examination of disease severity and quality of life.

Nutritional and body weight recommendations for cardiovascular diseases are well established, yet there are no equivalent guidelines for peripheral arterial disease (PAD). This cross-sectional study measured the prevalence of cardiovascular-related nutritional and body composition risk factors in sixty PAD patients and their association with PAD severity. A diet that exceeds daily recommended intake of fat and that falls short of recommended intakes of fiber, folate, and vitamin D was associated with increased leg pain and walking difficulty. Increased body fat and waist circumference were associated with diminished walking ability and poorer psychosocial quality of life. Future prospective investigations are merited to inform both PAD clinical care and disease management guidelines.

Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors.

OBJECTIVES: Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule stabilization inducing tumor and tumor endothelial cell apoptosis. The purpose of this study was to determine the optimal tolerated dose (OTD) of the combination of pazopanib and ixabepilone for the treatment of metastatic previously treated solid tumors. METHODS: Dose escalation started at 32 mg/m of ixabepilone and increased to 40 mg/m. Pazopanib was administered initially at 400 mg and escalated at 200 mg increments up to 800 mg. Pharmacokinetic analysis assessed effect of ixabepilone on pazopanib metabolism. Correlative studies evaluated changes in angiogenic cytokines. RESULTS: Thirty-one patients (20 male and 11 female; median age, 58 y) with ECOG PS of 0 or 1 were enrolled. Three patients had dose-limiting toxicities (fatigue and neutropenia) at dose level 2 (ixabepilone 40 mg/m and pazopanib 400 mg), and therefore the ixabepilone dose was decreased (32 mg/m) before escalating pazopanib to levels 3 and 4. One patient had a dose-limiting toxicity (thrombocytopenia) at dose level 4 (ixabepilone 32 mg/m and pazopanib 800 mg). Dose level 3 was determined to be the OTD (pazopanib 600 mg and ixabepilone 32 mg/m). The most common toxicities were cytopenias. A significant decrease in the level of sE-selectin was associated with improvement in progression free survival. CONCLUSIONS: The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.

Monitoring tobacco-specific N-nitrosamines and nicotine in novel smokeless tobacco products: findings from round II of the new product watch.

INTRODUCTION: Analysis of novel smokeless tobacco products purchased in Round I of the New Product Watch (NPW)-a national tobacco monitoring network-demonstrated that some tobacco constituents vary not only across various brands but also regionally and over time within the same product. In this study, we analyzed snus and dissolvable tobacco products that were purchased in Round II of the NPW. METHODS: We analyzed tobacco-specific N-nitrosamines (TSNA) and nicotine in snus and dissolvable tobacco products that were purchased in various regions of the country during the spring and summer of 2011. The results were compared against the Round I data, across different U.S. regions, and among products. RESULTS: A total of 216 samples were received from different states representing 6 regions of the country. Compared with the previous analyses, TSNA levels increased significantly in Marlboro and Camel Snus and some dissolvable Camel products. The levels of unprotonated nicotine in Marlboro Snus and Camel Snus in this study were not different from Round I but varied significantly by regions; the differences between the highest and the lowest average regional levels were ~3.2-fold in Marlboro Snus ~1.7-fold in Camel Snus. CONCLUSIONS: Our results indicate that some novel smokeless tobacco products contain TSNA at the levels found in the conventional moist snuff. Observation of regional variations in unprotonated nicotine content in both Round I and Round II of NPW suggest that manufacturers may tailor the levels of this constituent consistently to different regions.

Motivating underserved Vietnamese Americans to obtain colorectal cancer screening: evaluation of a culturally tailored DVD intervention.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death among Vietnamese Americans, yet screening remains underutilized. We investigated the effectiveness of a culturally tailored DVD intervention in promoting CRC screening among unscreened Vietnamese Americans age 50 and over. MATERIALS AND METHODS: Using a community-based participatory research approach, we conducted a trial comparing twenty-eight subjects who received a mailed DVD in Vietnamese, with twenty-eight subjects who received a mailed brochure in Vietnamese. Subjects completed telephone surveys at baseline, One-month, and one-year. The primary outcome was receipt of screening. Secondary measures were participants' knowledge, attitudes, and beliefs about CRC screening. Two focus groups explored the intervention's acceptability and effectiveness. RESULTS: At one year, CRC screening rates of 57.1% and 42.9% were observed in experimental and control group respectively (p=0.42), Subjects in both groups showed increased knowledge about CRC after one month. Focus group findings revealed that the DVD was an effective method of communicating information and would help promote screening. CONCLUSIONS: The findings suggest that culturally tailored, linguistically appropriate content is more important than the type of media used. This relatively low intensity, low cost intervention utilizing a DVD can be another useful method for outreach to the often hard-to-reach unscreened population.

Multiple-type human papillomavirus (HPV) infections: a cross-sectional analysis of the prevalence of specific types in 309,000 women referred for HPV testing at the time of cervical cytology.

OBJECTIVES: To determine the frequency of multiple-type cervical human papillomavirus (HPV) infections, and whether any types are involved in multiple-type infections more or less frequently than might be expected if these infections occur randomly. METHODS: In this retrospective analysis of type-specific HPV testing, results from women 18 to 65 years old with samples collected between July 2007 and May 2011 were considered.Multivariate logistic regression analysis was used to model the presence of each of the 24 most prevalent HPV types, adjusting for one other HPV type, age, laboratory region, and age-by-region interactions. RESULTS: Human papillomavirus infection was present in 74,543 (24.1%) of 309,471 women and 65,492 (21.1%) were positive for one of the top 24 most prevalent HPV types. The most common HPV type was type 16, occurring in 4.1% of the entire sample. A total of 14,181 women were positive for 2 or more HPV types (4.6% of entire sample and 19.0% of HPV-positive sample). Two-way HPV type comparisons were analyzed. Types 52, 53, 81, and 83 were more likely to occur in multiple infections with other types; and types 16, 58, and 66 were less likely to occur in multiple infections with other types. Human papillomavirus types 72 and 81 have the strongest positive relationship (odds ratio, 5.2; 95% confidence interval, 3.6-7.4). Human papillomavirus types 33 and 66 have the strongest negative relationship (odds ratio, 0.4; 95% confidence interval, 0.2-0.6). CONCLUSIONS: In this population, multiple-type HPV infections were present in 4.6% of all women. Our findings suggest that there may be both competitive and cooperative interactions between HPV types.

Current fit of medial and lateral unicompartmental knee arthroplasty.

Whether failure in unicompartmental knee arthroplasty (UKA) is related to implant design remains unclear. We hypothesize that current available UKAs fit within 2 mm. Forty-eight CTs of cadaveric knees were compared to current available UKA brands. Overall no-fit compared to at least one component within 2 mm is high (91.7%) and worse for males (100%) compared to females (833%). Good fit was observed for the medial but not for the lateral tibia plateau. Seven males (29.2%) had larger dimensions of more than 2 mm. For the widest UKA brand, 12 (57%) males and 2 females (8. 3%) had lateral femoral condyles 3 mm larger. Current UKA's in our sample population fit less on the lateral tibia and on femoral condyles.

Phase II study of topotecan and bevacizumab in advanced, refractory non--small-cell lung cancer.

BACKGROUND: This clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non--small-cell lung cancer in a second-line setting. PATIENT AND METHODS: Patients aged 18 years old and older received topotecan (4.0 mg/m(2)) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan. RESULTS: Forty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression. CONCLUSION: Bevacizumab in combination with topotecan as a salvage therapy for metastatic non--small-cell lung cancer is well tolerated and is worthy of further investigation.

Risk factors for revision of primary total hip arthroplasty: a systematic review.

BACKGROUND: Numerous papers have been published examining risk factors for revision of primary total hip arthroplasty (THA), but there have been no comprehensive systematic literature reviews that summarize the most recent findings across a broad range of potential predictors. METHODS: We performed a PubMed search for papers published between January, 2000 and November, 2010 that provided data on risk factors for revision of primary THA. We collected data on revision for any reason, as well as on revision for aseptic loosening, infection, or dislocation. For each risk factor that was examined in at least three papers, we summarize the number and direction of statistically significant associations reported. RESULTS: Eighty-six papers were included in our review. Factors found to be associated with revision included younger age, greater comorbidity, a diagnosis of avascular necrosis (AVN) as compared to osteoarthritis (OA), low surgeon volume, and larger femoral head size. Male sex was associated with revision due to aseptic loosening and infection. Longer operating time was associated with revision due to infection. Smaller femoral head size was associated with revision due to dislocation. CONCLUSIONS: This systematic review of literature published between 2000 and 2010 identified a range of demographic, clinical, surgical, implant, and provider variables associated with the risk of revision following primary THA. These findings can inform discussions between surgeons and patients relating to the risks and benefits of undergoing total hip arthroplasty.

Risk factors for posttraumatic heterotopic ossification of the elbow: case-control study.

PURPOSE: Heterotopic ossification (HO) is well-known after surgical repair of elbow fractures, but little is known about risk factors for its development in these patients. The purpose of this study was to define factors associated with development of HO. METHODS: We used a prospective fracture registry collected in 2 Level I trauma centers and medical chart review to examine all elbow fractures treated surgically between 2002 and 2009. We determined which of these patients developed HO with an impact on range of motion (Hastings class II and III). We conducted a matched case-control study to examine factors associated with risk of HO. We used conditional logistic regression to compare occurrences of risk factors between cases and controls, matched by fracture type, age, and sex. RESULTS: Our database contained 786 elbow fractures treated surgically. Of these, 55 developed clinically relevant HO. The risk of HO varied among types of elbow fractures, with combined olecranon and radial head fractures having no HO and floating elbows (fractures on both sides of the elbow joint) having the highest incidence of HO at 36%. In multiple conditional logistic regression, risk factors for the development of HO were days to surgery, with subjects waiting 8 or more days having 12 times the odds of HO than subjects having surgery within a day of injury, and time to postoperative mobilization, with subjects who had at least 15 days to mobilization having greater odds of HO than those who had less than 7 days to mobilization. CONCLUSIONS: Heterotopic ossification of the elbow occurs frequently after surgical repair of elbow fractures, with an incidence of 7% in this registry. In the case-control sample, conditions associated with development of HO included longer time to surgery and longer time to mobilization after surgery.

Analyzing variability in pain management using electronic health record data.

Variability in pain management processes may affect outcomes. Researchers collected pain management documentation from electronic health record systems of 3 hospitals and constructed process and outcome variables. Simple linear regressions revealed that relationships exist between increased pain variability and less frequent assessment and more frequent intervention, identifying targeted areas for improvement. Researchers demonstrated the use of the electronic record output for improvement purposes.

Time course of DNA adduct formation in peripheral blood granulocytes and lymphocytes after drinking alcohol.

Alcohol consumption is an established risk factor for cancers of the head and neck, colorectum, liver and female breast. Acetaldehyde, the primary metabolite of ethanol, is suspected to play a major role in alcohol-related carcinogenesis. Acetaldehyde binds to DNA resulting in formation of adducts. DNA adducts are involved in mutagenesis and carcinogenesis. N (2)-Ethylidenedeoxyguanosine (N (2)-ethylidene-dGuo) is the major adduct formed in this reaction. Studies have shown an association between alcohol drinking and levels of this DNA adduct, suggesting its potential use as a biomarker for studying alcohol-related carcinogenesis. However, there are no reports on the kinetics of formation and repair of N (2)-ethylidene-dGuo after alcohol consumption. Therefore, we investigated levels of N (2)-ethylidene-dGuo in DNA from human peripheral blood cells at several time points after consumption of increasing doses of alcohol. Ten healthy non-smokers were recruited and asked to abstain from alcohol consumption except for the study doses. The subjects were given measured doses of alcohol once a week for 3 weeks, targeting increasing blood alcohol levels. Blood was collected at several time points before and after each dose, DNA was isolated from granulocytes and lymphocytes and N (2)-ethylidene-dGuo was quantified as its NaBH(3)CN reduction product N ( 2 )-ethyldeoxyguanosine by liquid chromatography-electrospray ionisation-tandem mass spectrometry. Significant increases in N (2)-ethylidene-dGuo were observed after all doses and in both cell types. However, there was substantial intraindividual variability, indicating that there are other important sources of this adduct in peripheral blood DNA. Further studies are needed to better understand the origins of N (2)-ethylidene-dGuo in blood cells, the exposures it reflects, and thus its potential use as a marker of alcohol's genotoxic effects.

Kinetics of DNA adduct formation in the oral cavity after drinking alcohol.

BACKGROUND: Alcohol consumption is one of the top 10 risks for the worldwide burden of disease and an established cause of head and neck cancer, as well as cancer at other sites. Acetaldehyde, the major metabolite of ethanol, reacts with DNA to produce adducts, which are critical in the carcinogenic process and can serve as biomarkers of exposure and, possibly, of disease risk. Acetaldehyde associated with alcohol consumption is considered "carcinogenic to humans." We have previously developed the technology to quantify acetaldehyde-DNA adducts in human tissues, but there are no studies in the literature defining the formation and removal of acetaldehyde-DNA adducts in people who consumed alcohol. METHODS: We investigated levels of N(2)-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at several time points after consumption of increasing alcohol doses. Ten healthy nonsmokers were dosed once a week for three weeks. Mouthwash samples were collected before and at several time points after the dose. N(2)-Ethylidene-dGuo was measured as its NaBH(3)CN reduction product N(2)-ethyl-dGuo by liquid chromatography-electrospray-tandem mass spectrometry. RESULTS: N(2)-ethylidene-dGuo levels increased as much as 100-fold from baseline within 4 hours after each dose for all subjects and in a dose-responsive manner (P = 0.001). CONCLUSION: These results show an effect of alcohol on oral cell DNA adduct formation, strongly supporting the key role of acetaldehyde in head and neck cancer caused by alcohol drinking. IMPACT: Our results provide some of the first conclusive evidence linking exposure to a lifestyle carcinogen and kinetics of DNA adduct formation in humans.

Increased pouch sizes and resulting changes in the amounts of nicotine and tobacco-specific N-nitrosamines in single pouches of Camel Snus and Marlboro Snus.

INTRODUCTION: Initial analyses of the novel smokeless tobacco products Camel Snus and Marlboro Snus demonstrated that these products contain relatively low amounts of nicotine and the carcinogenic tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as compared with traditional smokeless products. It is unknown whether the modifications in packaging, flavors, and pouch sizes that occurred for both Camel Snus and Marlboro Snus since their first introduction to the market were accompanied by any changes in nicotine or nitrosamine levels. METHODS: We examined the available data on nicotine and NNN and NNK levels in 60 samples of Camel Snus and 87 samples of Marlboro Snus that were analyzed in our laboratory between 2006 and 2010. RESULTS: Due to the increase in pouch size, the amounts of total nicotine, unprotonated nicotine, and the sum of NNN and NNK present in the large Camel Snus pouches released in 2010 are 1.9-fold, 2.4-fold, and 3.3-fold higher, respectively, than in the original smaller pouches that entered the market in 2006. Total and unprotonated nicotine content in the current version of Marlboro Snus pouches are 2.1-fold and 1.9-fold higher, respectively, and the sum of NNN and NNK is 1.5-fold lower than in the original version. CONCLUSIONS: We observed an increase in nicotine content in single portions of Camel Snus and Marlboro Snus, and an increase in tobacco-specific N-nitrosamine content in single portions of Camel Snus, due to the increases in pouch size that occurred between 2006 and 2010. This finding stresses the importance of tobacco product regulation and ingredient disclosures.

Determining the Probability Distribution and Evaluating Sensitivity and False Positive Rate of a Confounder Detection Method Applied To Logistic Regression.

BACKGROUND: In epidemiologic studies researchers are often interested in detecting confounding (when a third variable is both associated with and affects associations between the outcome and predictors). Confounder detection methods often compare regression coefficients obtained from "crude" models that exclude the possible confounder(s) and "adjusted" models that include the variable(s). One such method compares the relative difference in effect estimates to a cutoff of 10% with differences of at least 10% providing evidence of confounding. METHODS: In this study we derive the asymptotic distribution of the relative change in effect statistic applied to logistic regression and evaluate the sensitivity and false positive rate of the 10% cutoff method using the asymptotic distribution. We then verify the results using simulated data. RESULTS: When applied to a logistic regression models with a dichotomous outcome, exposure, and possible confounder, we found the 10% cutoff method to have an asymptotic lognormal distribution. For sample sizes of at least 300 the authors found that when confounding existed, over 80% of models had >10% changes in odds ratios. When the confounder was not associated with the outcome, the false positive rate increased as the strength of the association between the predictor and confounder increased. When the confounder and predictor were independent of one another, false positives were rare (most < 10%). CONCLUSIONS: Researchers must be aware of high false positive rates when applying change in estimate confounder detection methods to data where the exposure is associated with possible confounder variables.

Estimating proximity to care: are straight line and zipcode centroid distances acceptable proxy measures?

BACKGROUND: Spatial accessibility of healthcare may be measured by proximity of patient residence to health services, typically in driving distance or driving time. Precise driving distances and times are rarely available. Although straight line distances between zipcode centroids and between precise address locations are used as proxy measures for distance to care, the accuracy of these measures has received little study. METHODS: Among a cohort of Medicare beneficiaries, actual driving distances and times between patient residence and clinic were obtained from commercial software (MapQuest). We used a split-sample design to build and validate linear regression models that predict actual driving distances and times from estimated distances between zipcode centroids and between precise residential and hospital locations, adjusting for urban/suburban/rural residential status. RESULTS: On average, predicted driving distances and times were larger than actual values. Zipcode centroid distances alone predicted longer driving distances than observed values: rural +19% (3.2 miles), suburban +23% (3.7 miles), and urban +27% (2.0 miles). Predicted time was 36% (9.4 min) longer in rural, 32% (6.8 min) longer in suburban, and 38% (4.7 min) longer in urban areas than observed values. Including urban/suburban/rural categorization of residence improved the accuracy of predicted driving distance and time for suburban and urban areas but diminished accuracy for rural areas. Similar trends were observed for distance estimates from precise locations. CONCLUSIONS: Distances between zipcode centroids and precise residential/hospital locations provide reasonable estimates of driving distance and time for epidemiologic research. Estimates are improved for suburban and urban residences when data are augmented by urban categorization.

Maternal depressive symptoms and participation in early intervention services for young children.

Many young children with developmental delay who are eligible for early intervention (EI) services fail to receive them. We assessed the relationship between depressive symptoms in mothers, a potentially modifiable risk, and receipt of EI services by their eligible children. We conducted multivariable analyses of a nationally representative sample of children eligible for EI services at 24 months using data from the Early Childhood Longitudinal Study-Birth Cohort. Maternal depressive symptoms were assessed at 9 and 24 months. Birthweight <1,000 g, genetic and medical conditions associated with developmental delay, or low scores on measures of developmental performance defined EI eligibility. Service receipt was ascertained from parental self-report. Models were adjusted for sociodemographic and child risk. Among the 650 children who were eligible to receive EI services as infants, 33.2% of children whose mothers were depressed received services compared to 27.0% whose mothers were not depressed (aOR 1.8; 95% CI 0.8, 4.0). Among the 650 children who became eligible to receive services as toddlers, 13.0% of children whose mothers were depressed received services compared to 2.6% whose mothers were not depressed (aOR 4.6, 95% CI 1.5, 14.6). Among children receiving EI services, prevalence of depressive symptoms was 23.0% for mothers whose children became eligible as infants and 57.5% for mothers whose children became eligible as toddlers. Depressive symptoms in mothers of children eligible to receive EI services did not appear to limit participation. EI programs may be an appropriate setting in which to address maternal depressive symptoms.

Monitoring tobacco-specific N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: findings from Round 1 of the New Product Watch.

INTRODUCTION: Information on chemical composition of the new oral "spitless" smokeless tobacco products is scarce, and it is not clear whether there is some variability as a function of purchase place or time due to either unintended or intended manufacturing variations or other conditions. METHODS: We analyzed tobacco-specific N-nitrosamines (TSNA) and nicotine in Marlboro Snus, Camel Snus, and dissolvable Camel products Orbs, Sticks, and Strips that were purchased in various regions of the country during the summer of 2010. RESULTS: A total of 117 samples were received from different states representing six regions of the country. Levels of unprotonated nicotine in Marlboro Snus and Camel Snus varied significantly by regions, with the differences between the highest and the lowest average regional levels being relatively small in Marlboro Snus (∼1.3-fold) and large in Camel Snus (∼3-fold). Some regional variations in TSNA levels were also observed. Overall, Camel Snus had significantly higher TSNA levels than Marlboro Snus, and Camel Strips had the lowest TSNA levels among all novel products analyzed here. The amount of unprotonated nicotine in the dissolvable Camel products was comparable to the levels found in Marlboro Snus. CONCLUSIONS: Our study demonstrates some regional variations in the levels of nicotine and TSNA in Marlboro and Camel novel smokeless tobacco products. Continued monitoring of this category of products is needed as the existing products are being test marketed and modified, and new products are being introduced. This information is particularly important given its relevance to Food and Drug Administration regulation of tobacco products.

Beyond core measures: identifying modifiable risk factors for prevention of surgical site infection after elective total abdominal hysterectomy.

BACKGROUND: Despite adherence to the Centers for Medicare and Medicaid Services (CMS) core measures for preventing surgical site infections (SSI), our institution has a >10% rate of SSI after total abdominal hysterectomy (TAH), higher than the 90(th) percentile for SSI rates published in the 2009 National Healthcare Safety Network report. METHODS: A retrospective chart review was performed for patients who underwent elective TAH at a public safety net hospital in Denver from December 30, 2005, to March 9, 2010. The primary outcome was development of SSI within 30 days. A secondary outcome was adherence to CMS core measures. RESULTS: A total of 192 patients were included in the analysis, of whom 21 (10.9%) developed SSI. More than 95% had received antibiotics in the 60 min before surgical incision, and >90% received an appropriate antibiotic. Compliance with post-anesthesia care unit normothermia was equivalent in the SSI and non-SSI groups (81.0% vs. 75.2%; p=0.5588). Surgical site infection was associated with obesity (body mass index [BMI]≥30) (15.4% vs. 6.9%; p=0.0609), estimated blood loss≥500 mL (18.5% vs. 8.0%; p=0.0353), and receipt of a blood transfusion (28.6% vs. 10.5%; p=0.0183). In a multiple logistic regression model, obesity marginally increased the risk of SSI (odds ratio [OR] 2.55; 95% confidence interval [CI] 0.94-6.74), whereas blood transfusion was significantly associated with a higher risk of SSI (OR 3.58; 95% CI 1.21-10.62). CONCLUSIONS: Blood transfusion was associated with SSI after TAH in our population. As it is a modifiable risk factor, larger multi-center studies are needed to confirm this result and determine appropriate transfusion thresholds.

Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK.

INTRODUCTION: Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear. METHODS: We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents. RESULTS: Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. Consistent with delayed involution, mammary glands of transgenic animals displayed decreased STAT3 phosphorylation, a marker of early-stage involution. Notably, p38 MAPK, a pro-survival signaling mediator downstream of Brk, was activated in mammary glands of Brk transgenic relative to wt mice. Brk-dependent signaling to p38 MAPK was recapitulated by Brk overexpression in the HC11 murine mammary epithelial cell (MEC) line and human MEC, while Brk knock-down in breast cancer cells blocked EGF-stimulated p38 signaling. Additionally, human or mouse MECs expressing Brk exhibited increased anchorage-independent survival and resistance to doxorubicin. Finally, breast tumor biopsies were subjected to IHC analysis for co-expression of Brk and phospho-p38 MAPK; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK. CONCLUSIONS: These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways.