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author:("walleye, T")
1.  A practical approach to goal-directed echocardiography in the critical care setting 
Critical Care  2014;18(6):681.
Urgent cardiac ultrasound examination in the critical care setting is clinically useful. Application of goal-directed echocardiography in this setting is quite distinct from typical exploratory diagnostic comprehensive echocardiography, because the urgent critical care setting mandates a goal-directed approach. Goal-directed echocardiography most frequently aims to rapidly identify and differentiate the cause(s) of hemodynamic instability and/or the cause(s) of acute respiratory failure. Accordingly, this paper highlights 1) indications, 2) an easily memorized differential diagnostic framework for goal-directed echocardiography, 3) clinical questions that must be asked and answered, 4) practical issues to allow optimal image capture, 5) primary echocardiographic views, 6) key issues addressed in each view, and 7) interpretation of findings within the differential diagnostic framework. The most frequent indications for goal-directed echocardiography include 1) the spectrum of hemodynamic instability, shock, and pulseless electrical activity arrest and 2) acute respiratory failure. The differential diagnostic categories for hemodynamic instability can be remembered using the mnemonic ‘SHOCK’ (for Septic, Hypovolemic, Obstructive, Cardiogenic, and (K) combinations/other kinds of shock). RESP-F (for exacerbation of chronic Respiratory disease, pulmonary Embolism, ST changes associated with cardiac or pericardial disease, Pneumonia, and heart Failure) can be used for acute respiratory failure. The goals of goal-directed echocardiography in the unstable patient are: assessing global ventricular systolic function, identifying marked right ventricular and left ventricular enlargement, assessing intravascular volume, and the presence of a pericardial effusion. In an urgent or emergent setting, it is recommended to go directly to the best view, which is frequently the subcostal or apical view. The five views are the subcostal four-chamber view, subcostal inferior vena cava view, parasternal long axis view, parasternal short axis view, and the apical four chamber view. Always interpret goal-directed echocardiographic findings in the context of clinically available hemodynamic information. When goal-directed echocardiography is insufficient or when additional abnormalities are appreciated, order a comprehensive echocardiogram. Goal-directed echocardiography and comprehensive echocardiography are not to be used in conflict with each other.
PMCID: PMC4331439  PMID: 25672460
2.  Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer 
The New England journal of medicine  2014;371(2):107-118.
Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer.
In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.
After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women.
In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT numbers, NCT00066703 and NCT00066690, respectively.)
PMCID: PMC4175521  PMID: 24881463
3.  Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study 
Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival.
We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1–3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died.
In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1–3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10−8). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10−8 (odds ratio 0·56, 95% CI 0·45–0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45–0·69; likelihood ratio test p=3·4 × 10−9, after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined.
We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification.
European Commission and the Wellcome Trust.
PMCID: PMC4314768  PMID: 25533491
4.  Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: Design of the TEXT and SOFT trials 
Breast (Edinburgh, Scotland)  2013;22(6):10.1016/j.breast.2013.08.009.
In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen?
TEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization.
TEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up . To assess the AI question, exemestane+OFS versus tamoxifen+OFS, a combined analysis of TEXT and SOFT became the primary analysis (n=4717). The OFS question became the primary analysis from SOFT, the unique comparison of tamoxifen+OFS versus tamoxifen alone (n=2045). The first reports are anticipated in mid- and late-2014.
We present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer.
PMCID: PMC3855346  PMID: 24095609
premenopausal; endocrine-responsive; early breast cancer; adjuvant therapy; trial design
5.  Aging and the intramyocardial inflammatory response 
Critical Care  2014;18(6):638.
The sepsis-induced intramyocardial inflammatory response results in decreased ventricular function and myocardial damage. Chemokines such as monocyte chemoattractant protein-1 causally contribute to retention of intramyocardial mononuclear leukocytes and subsequent ventricular dysfunction during endotoxemic shock in mice and, importantly, this effect is age dependent. It is therefore useful to consider where monocyte chemoattractant protein-1 fits in the complex pathway leading to ventricular dysfunction during sepsis, why this might be an age-dependent effect, and what this implies for care of older sepsis patients.
PMCID: PMC4330602  PMID: 25672938
6.  Preventing Prescription Opioid Overdose Deaths 
Journal of General Internal Medicine  2013;28(10):1258-1259.
PMCID: PMC3785643  PMID: 23463455
7.  Metabolic changes in cardiomyocytes during sepsis 
Critical Care  2013;17(5):186.
Different types of shock induce distinct metabolic changes. The myocardium at rest utilizes free fatty acids as its primary energy source, a mechanism that changes to aerobic glycolysis during sepsis and is in contrast to hemorrhagic shock. The immune system also uses this mechanism, changing its substrate utilization to activate innate and adaptive cells. Cardiomyocytes share a number of features similar to antigen-presenting cells and may use this mechanism to augment the immune response at the reversible expense of cardiac function.
PMCID: PMC4056895  PMID: 24053782
8.  Is cannabis use associated with HIV drug and sex risk behaviors among Russian HIV-infected risky drinkers? 
Drug and alcohol dependence  2013;132(0):74-80.
While cannabis use has been associated with increased HIV drug and sex risk behaviors, its impact on risk behaviors among HIV-infected individuals has not yet been established.
This study examined data from Russian HIV-infected risky drinkers enrolled in a randomized controlled trial of a behavioral intervention. The primary independent variable was cannabis use (current [past 30 days use], recent past [use but not in past 30 days] vs. no past year use). Primary outcomes were needle sharing and number of unprotected sexual episodes. Secondary outcomes were drug injection, number of injections, and multiple sex partners. Longitudinal regression analyses controlled for age, gender, marital status, education, CD4 count, ART use, risky alcohol use, other drug use, depressive symptoms and randomization group.
Cannabis use was common with 20% current and 26% recent past use at baseline. In longitudinal analyses current, but not recent past, cannabis consumption was significantly associated with needle sharing (AOR 2.23 current vs. none, 95% CI: 1.46, 3.36), drug injection (AOR 3.05 current vs. none, 95% CI: 2.06, 4.53) and number of injections (adjusted IRR 1.50 current vs. none, 95% CI: 1.19, 1.89). Current and recent past cannabis use were significantly associated with multiple sex partners but not with number of unprotected sex episodes.
Cannabis use was associated with drug and sex risk behaviors among Russian HIV-infected risky drinkers. Inquiry about cannabis use among HIV-infected patients may reveal a patient group at higher risk for sex and drug use behaviors that lead to HIV transmission.
PMCID: PMC3726566  PMID: 23410616
Cannabis use; HIV; sex risk behavior; drug risk behavior; Russia
9.  Toward an Effective Long-Term Strategy for Preventing Motor Vehicle Crashes and Injuries 
Casualties due to motor vehicle crashes (MVCs) include some 40,000 deaths each year in the United States and one million deaths worldwide. One strategy that has been recommended for improving automobile safety is to lower speed limits and enforce them with speed cameras. However, motor vehicles can be hazardous even at low speeds whereas properly protected human beings can survive high-speed crashes without injury. Emphasis on changing driver behavior as the focus for road safety improvements has been largely unsuccessful; moreover, drivers today are increasingly distracted by secondary tasks such as cell phone use and texting. Indeed, the true limiting factor in vehicular safety is the capacity of human beings to sense and process information and to make rapid decisions. Given that dramatic reductions in injuries and deaths from MVCs have occurred over the past century due to improvements in safety technology, despite increases in the number of vehicles on the road and miles driven per vehicle, we propose that an effective long-term strategy for reducing MVC-related injury would be continued technological innovation in vehicle design, aimed at progressively removing the driver from routine operational decision-making. Once this is achieved, high rates of speed could be achieved on open highways, with minimal risk of crashes and injury to occupants and pedestrians.
PMCID: PMC4143853  PMID: 25116634
injury; prevention; safety; roads; technology; robotics
10.  Punitive policing and associated substance use risks among HIV-positive people in Russia who inject drugs 
Drug law enforcement is part of the HIV risk environment among people who inject drugs (PWID). Punitive policing practices such as extrajudicial arrests for needle possession and police planting of drugs have been described anecdotally in Russia, but these experiences and their associations with risky drug behaviours have not been quantified. This study aims to quantify the burden of extrajudicial police arrests among a cohort of HIV-positive PWID in Russia and to explore its links to drug-related health outcomes.
In a cross-sectional study of 582 HIV-positive people with lifetime injection drug use (IDU) in St. Petersburg, Russia, we estimated the prevalence of self-reported extrajudicial police arrests. We used multiple logistic regression to evaluate associations between arrests and the following outcomes: overdose, recent IDU and receptive needle sharing.
This cohort's mean age was 29.8 years, 60.8% were male; 75.3% reported non-fatal drug overdose, 50.3% recent IDU and 47.3% receptive needle sharing. Extrajudicial arrests were reported by more than half (60.5%, 95% confidence interval [CI]: 56.5–64.5) and were associated with higher odds of non-fatal drug overdose (AOR 1.52, 95% CI: 1.02–2.25) but not with recent IDU (AOR 1.17, arrests were associated with receptive needle sharing (AOR 1.84, 95% CI: 1.09–3.09).
Extrajudicial police arrests were common among this cohort of Russian HIV-positive PWID and associated with non-fatal overdose and, among those with recent IDU, receptive needle sharing. As a part of the HIV risk environment of PWIDs, these practices might contribute to HIV transmission and overdose mortality. Further research is needed to relate these findings to the operational environment of law enforcement and to better understand how police interventions among PWIDs can improve the HIV risk environment.
PMCID: PMC4093768  PMID: 25014321
human rights; police involvement; PLHA; injection drug use; key populations; Russian Federation
11.  Transcriptome and methylome profiling reveals relics of genome dominance in the mesopolyploid Brassica oleracea 
Genome Biology  2014;15(6):R77.
Brassica oleracea is a valuable vegetable species that has contributed to human health and nutrition for hundreds of years and comprises multiple distinct cultivar groups with diverse morphological and phytochemical attributes. In addition to this phenotypic wealth, B. oleracea offers unique insights into polyploid evolution, as it results from multiple ancestral polyploidy events and a final Brassiceae-specific triplication event. Further, B. oleracea represents one of the diploid genomes that formed the economically important allopolyploid oilseed, Brassica napus. A deeper understanding of B. oleracea genome architecture provides a foundation for crop improvement strategies throughout the Brassica genus.
We generate an assembly representing 75% of the predicted B. oleracea genome using a hybrid Illumina/Roche 454 approach. Two dense genetic maps are generated to anchor almost 92% of the assembled scaffolds to nine pseudo-chromosomes. Over 50,000 genes are annotated and 40% of the genome predicted to be repetitive, thus contributing to the increased genome size of B. oleracea compared to its close relative B. rapa. A snapshot of both the leaf transcriptome and methylome allows comparisons to be made across the triplicated sub-genomes, which resulted from the most recent Brassiceae-specific polyploidy event.
Differential expression of the triplicated syntelogs and cytosine methylation levels across the sub-genomes suggest residual marks of the genome dominance that led to the current genome architecture. Although cytosine methylation does not correlate with individual gene dominance, the independent methylation patterns of triplicated copies suggest epigenetic mechanisms play a role in the functional diversification of duplicate genes.
PMCID: PMC4097860  PMID: 24916971
12.  Macrophage gene expression in adipose tissue is associated with insulin sensitivity and serum lipid levels independent of obesity 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20443.
Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances.
Design and Methods
Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group.
The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group.
Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
PMCID: PMC3763968  PMID: 23512687
13.  Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumours 
Cancer prevention research (Philadelphia, Pa.)  2013;6(12):10.1158/1940-6207.CAPR-13-0104.
Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterised. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium’s HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly epigenetically regulated in this tumour type.
Using a linear model for microarray data we identified 1610 differentially methylated autosomal CpG sites with 809 CpG sites (representing 603 genes) being hypermethylated and 801 CpG sites (representing 712 genes) being hypomethylated in cholangiocarcinoma versus adjacent normal tissues (false discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12 and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102).
Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors.
PMCID: PMC3855864  PMID: 24089088
DNA methylation; cholangiocarcinoma; cancer; stem cells; HOX
14.  Introduction 
PMCID: PMC3982657  PMID: 24711497
Bertram Hopkinson; Hopkinson bar; blast; impact; high strain rate
15.  The Encyclopedia of Life v2: Providing Global Access to Knowledge About Life on Earth 
The Encyclopedia of Life (EOL, aims to provide unprecedented global access to a broad range of information about life on Earth. It currently contains 3.5 million distinct pages for taxa and provides content for 1.3 million of those pages. The content is primarily contributed by EOL content partners (providers) that have a more limited geographic, taxonomic or topical scope. EOL aggregates these data and automatically integrates them based on associated scientific names and other classification information. EOL also provides interfaces for curation and direct content addition. All materials in EOL are either in the public domain or licensed under a Creative Commons license. In addition to the web interface, EOL is also accessible through an Application Programming Interface.
In this paper, we review recent developments added for Version 2 of the web site and subsequent releases through Version 2.2, which have made EOL more engaging, personal, accessible and internationalizable. We outline the core features and technical architecture of the system. We summarize milestones achieved so far by EOL to present results of the current system implementation and establish benchmarks upon which to judge future improvements.
We have shown that it is possible to successfully integrate large amounts of descriptive biodiversity data from diverse sources into a robust, standards-based, dynamic, and scalable infrastructure. Increasing global participation and the emergence of EOL-powered applications demonstrate that EOL is becoming a significant resource for anyone interested in biological diversity.
PMCID: PMC4031434  PMID: 24891832
16.  Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study 
BMC Public Health  2014;14:297.
One approach to preventing opioid overdose, a leading cause of premature, preventable mortality, is to provide overdose education and naloxone distribution (OEND). Two outstanding issues for OEND implementation include 1) the dissemination of OEND training from trained to untrained community members; and 2) the concern that OEND provides active substance users with a false sense of security resulting in increased opioid use.
To compare overdose rescue behaviors between trained and untrained rescuers among people reporting naloxone rescue kit use; and determine whether heroin use changed after OEND, we conducted a retrospective cohort study among substance users in the Massachusetts OEND program from 2006 to 2010. We used chi square and t-test statistics to compare the differences in overdose management characteristics among overdoses managed by trained versus untrained participants. We employed Wilcoxon signed rank test to compare median difference among two repeated measures of substance use among participants with drug use information collected more than once.
Among 4,926 substance-using participants, 295 trained and 78 untrained participants reported one or more rescues, resulting in 599 rescue reports. We found no statistically significant differences in help-seeking (p = 0.41), rescue breathing (p = 0.54), staying with the victim (p = 0.84) or in the success of naloxone administration (p = 0.69) by trained versus untrained rescuers. We identified 325 OEND participants who had drug use information collected more than once. We found no significant overall change in the number of days using heroin in past 30 days (decreased 38%, increased 35%, did not change 27%, p = 0.52).
Among 4926 substance users who participated in OEND, 373(7.6%) reported administering naloxone during an overdose rescue. We found few differences in behavior between trained and untrained overdose rescuers. Prospective studies will be needed to determine the optimal level of training and whether naloxone rescue kits can meet an over-the-counter standard. With no clear evidence of increased heroin use, this concern should not impede expansion of OEND programs or policies that support them.
PMCID: PMC4004504  PMID: 24684801
Overdose; Opioids; Bystander naloxone; Rescue; People who use drugs
17.  China Tuberculosis Policy at Crucial Crossroads: Comparing the Practice of Different Hospital and Tuberculosis Control Collaboration Models Using Survey Data 
PLoS ONE  2014;9(3):e90596.
Currently three hospital and tuberculosis (TB) collaboration models exist in China: the dispensary model where TB has to be diagnosed and treated in TB dispensaries, the specialist model where TB specialist hospital also treat TB patients, and the integrated model where TB diagnosis and treatment is integrated into a general hospital. The study compared effects of the three models through exploring patient experience in TB diagnosis and treatment.
We selected two sites in each model of TB service in four provinces of China. In each site, 50 patients were selected from TB patient registries for a structured questionnaire survey, with a total of 293 patients recruited. All participants were newly registered uncomplicated TB cases without any major complications or resistance to first-line anti-TB drugs, and having successfully completed treatment. Diagnostic and treatment procedures were reviewed from medical charts of the surveyed patients to compare with national guidelines.
Specialist sites had the highest patient expenditure, hospitalization rates and mostly used second-line anti-TB drugs, while the integrated model reported the opposite. The median health expenditure was USD 1,499 for the specialist sites and USD 306 for the integrated sites, with 83% and 15% patients respectively having unnecessary hospitalization. 74% of the specialist sites and 19% of the integrated sites used second-line anti-TB drugs. Mixed results were identified in the two dispensary sites. One site had median health expenditure of USD 138 with 12% of patients hospitalized, while the other had USD 912 and 65% respectively.
The study observed prohibitive financial expenditure and a high level of deviation from national guidelines in all sites, which may be related to the profit-seeking behavior of public hospitals. The study supports the integrated model as the better policy option for future TB health reform in China.
PMCID: PMC3951218  PMID: 24621996
18.  Qualitative evaluation of care plans for Canadian breast and head-and-neck cancer survivors 
Current Oncology  2014;21(1):e18-e28.
Survivorship care plans (scps) have been recommended as a way to ease the transition from active cancer treatment to follow-up care, to reduce uncertainty for survivors in the management of their ongoing health, and to improve continuity of care. The objective of the demonstration project reported here was to assess the value of scps for cancer survivors in western Canada.
The Alberta CancerBridges team developed, implemented, and evaluated scps for 36 breast and 21 head-and-neck cancer survivors. For the evaluation, we interviewed 12 of the survivors, 9 nurses who delivered the scps, and 3 family physicians who received the scps (n = 24 in total). We asked about satisfaction, usefulness, emotional impact, and communication value. We collected written feedback from the three groups about positive aspects of the scps and possible improvements (n = 85). We analyzed the combined data using qualitative thematic analysis.
Survivors, nurses, and family physicians agreed that scps could ease the transition to survivorship partly by enhancing communication between survivors and care providers. Survivors appreciated the individualized attention and the comprehensiveness of the plans. They described positive emotional impacts, but wanted a way to ensure that their physicians received the scps. Nurses and physicians responded positively, but expressed concern about the time required to implement the plans. Suggestions for streamlining the process included providing survivors with scp templates in advance, auto-populating the templates for the nurses, and creating summary pages for physicians.
The results suggest ways in which scps could help to improve the transition to cancer survivorship and provide starting points for larger feasibility studies.
PMCID: PMC3921045  PMID: 24523618
Care plans; survivorship; communication; breast cancer; head-and-neck cancer; qualitative analysis
19.  Definition of molecular determinants of prostate cancer cell bone extravasation 
Cancer research  2012;73(2):942-952.
Advanced prostate cancer (PCa) commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. PCa cells roll on E-selectin+ BMEC through E-selectin ligand-binding interactions under shear flow, and PCa cells exhibit firm adhesion to BMEC via β1, β4 and αVβ3 integrins in static assays. However, whether these discrete PCa cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Herein, we describe how metastatic PCa cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. PCa cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic PCa tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. PCa cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1 and Rap1 were constitutively active. In homing studies, PCa cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases (α1,3 FT) in transgenic adenoma of mouse prostate (TRAMP) mice dramatically reduced PCa incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins and Rac/Rap1 GTPases in mediating PCa cell homing and entry into bone and offer new insight on the role of α1,3 fucosylation in PCa development.
PMCID: PMC3548951  PMID: 23149920
fucosyltransferases; integrins; prostate cancer; E-selectin; homing
20.  Changes in pulmonary tuberculosis prevalence: evidence from the 2010 population survey in a populous province of China 
This paper reports findings from the prevalence survey conducted in Shandong China in 2010, a province with a population of 94 million. This study aimed to estimate TB prevalence of the province in 2010 in comparison with the 2000 survey; and to compare yields of TB cases from different case finding approaches.
A population based, cross-sectional survey was conducted using multi-stage random cluster sampling. 54,279 adults participated in the survey with a response rate of 96%. Doctors interviewed and classified participants as suspected TB cases if they presented with persistent cough, abnormal chest X-ray (CXRAY), or both. Three sputum specimens of all suspected cases were collected and sent for smear microscopy and culture.
Adjusted prevalence rate of bacteriologically confirmed cases was 34 per 100,000 for adults in Shandong in 2010. Compared to the 2000 survey, TB prevalence has declined by 80%. 53% of bacteriologically confirmed cases did not present persistent cough. The yield of bacteriologically confirmed cases was 47% by symptom screening and 95% by CXRAY. Over 50% of TB cases were among over 65’s.
The prevalence rate of bacteriologically confirmed cases was significantly reduced compared with 2000. The survey raised challenges to identify TB cases without clear symptoms.
PMCID: PMC3890533  PMID: 24410932
Tuberculosis; Population based prevalence survey; Case finding; China
21.  Nondisclosure of HIV Infection to Sex Partners and Alcohol’s Role: A Russian Experience 
AIDS and behavior  2013;17(1):390-398.
Nondisclosure of one’s HIV infection to sexual partners obviates safer sex negotiations and thus jeopardizes HIV transmission prevention. The role of alcohol use in the disclosure decision process is largely unexplored. This study assessed the association between alcohol use and recent nondisclosure of HIV serostatus to sex partners by HIV-infected risky drinkers in St. Petersburg, Russia. Approximately half (317/605; 52.4 %) reported not having disclosed their HIV serostatus to all partners since awareness of infection. Using three separate GEE logistic regression models, we found no significant association between alcohol dependence, risky alcohol use (past 30 days), or alcohol use at time of sex (past 30 days) with recent (past 3 months) nondisclosure (AOR [95 %CI] 0.81 [0.55, 1.20], 1.31 [0.79, 2.17], 0.75 [0.54, 1.05], respectively). Alcohol use at time of sex was associated with decreased odds of recent nondisclosure among seroconcordant partners and among casual partners. Factors associated with nondisclosure were relationship with a casual partner, a serodiscordant partner, multiple sex partners, awareness of HIV diagnosis less than 1 year, and a lifetime history of sexually transmitted disease. Nondisclosure of HIV status to sex partners is common among HIV-infected Russians, however alcohol does not appear to be a predictor of recent disclosure.
PMCID: PMC3634358  PMID: 22677972
Nondisclosure; Disclosure; HIV; Russia; Alcohol
22.  Cytokines and Signaling Molecules Predict Clinical Outcomes in Sepsis 
PLoS ONE  2013;8(11):e79207.
Inflammatory response during sepsis is incompletely understood due to small sample sizes and variable timing of measurements following the onset of symptoms. The vasopressin in septic shock trial (VASST) compared the addition of vasopressin to norepinephrine alone in patients with septic shock. During this study plasma was collected and 39 cytokines measured in a 363 patients at both baseline (before treatment) and 24 hours. Clinical features relating to both underlying health and the acute organ dysfunction induced by the severe infection were collected during the first 28 days of admission.
Cluster analysis of cytokines identifies subgroups of patients at differing risk of death and organ failure.
Circulating cytokines and other signaling molecules were measured using a Luminex multi-bead analyte detection system. Hierarchical clustering was performed on plasma values to create patient subgroups. Enrichment analysis identified clinical outcomes significantly different according to these chemically defined patient subgroups. Logistic regression was performed to assess the importance of cytokines for predicting patient subgroups.
Plasma levels at baseline produced three subgroups of patients, while 24 hour levels produced two subgroups. Using baseline cytokine data, one subgroup of 47 patients showed a high level of enrichment for severe septic shock, coagulopathy, renal failure, and risk of death. Using data at 24 hours, a larger subgroup of 81 patients that largely encompassed the 47 baseline subgroup patients had a similar enrichment profile. Measurement of two cytokines, IL2 and CSF2 and their product were sufficient to classify patients into these subgroups that defined clinical risks.
A distinct pattern of cytokine levels measured early in the course of sepsis predicts disease outcome. Subpopulations of patients have differing clinical outcomes that can be predicted accurately from small numbers of cytokines. Design of clinical trials and interventions may benefit from consideration of cytokine levels.
PMCID: PMC3828333  PMID: 24244449
24.  Cardiovascular disease risk reduction in rural China: a clustered randomized controlled trial in Zhejiang 
Trials  2013;14:354.
Cardiovascular disease (CVD) is a major cause of death in China. Despite government efforts, the majority of hypertensive and diabetic patients in China do not receive proper treatment. Reducing CVD events requires long-term care that is proactive, patient-centred, community-based, and sustainable. We have designed a package of interventions for patients at high risk of CVD to be implemented by family doctors based in township hospitals (providers of primary care) in rural Zhejiang, China. This trial aims to determine whether the systematic CVD risk reduction package results in reduced CVD events among patients at risk of CVD compared with usual care, and whether the package is cost-effective and suitable for routine implementation and scale-up.
This is a prospective, open-label, cluster randomized controlled trial (RCT) with blinded data analysis. The trial will randomize 67 township hospitals with 31,708 participants in three counties in Zhejiang Province. Participants will be identified from existing health records and will comprise adults aged 50 to 74 years, with a calculated 10-year CVD risk of 20% or higher, or diabetes. In the intervention arm, participants will receive a package of interventions including: 1) healthy lifestyle counseling (smoking cessation, and salt, oil, and alcohol reduction); 2) prescription of a combination of drugs (antihypertensives, aspirin, and statin); and 3) adherence support for drug compliance and healthy lifestyle change. In the control arm, participants will receive usual care for hypertension and diabetes management at individual clinicians’ discretion. The primary outcome is the incidence of severe CVD events over 24 months of follow-up. All CVD events will be defined according to the World Health Organization (WHO) monitoring of trends and determinants in cardiovascular disease (MONICA) definitions, diagnosed at the county hospital or higher level, and reported by the Zhejiang surveillance system. Secondary outcomes include: mean systolic and diastolic blood pressure, blood glucose, serum total cholesterol (TC), and adherence to appointments, and drugs and lifestyle changes.
This trial focuses on risk reduction of CVD rather than specific diseases. It is not designed to compare therapeutic and healthy lifestyle interventions, but rather their combined effects in primary care settings. Through the trial, we intend to understand the effectiveness of the comprehensive CVD reduction package in routine practice. We also intend to understand the barriers and facilitators to implementing the package, and thus to advise on policy and practice change.
Trial registration
Current Controlled Trials: ISRCTN58988083
PMCID: PMC4015636  PMID: 24160442
Cardiovascular disease; Risk; Events; Randomized controlled trial; Primary care
25.  Delivering enhanced cardiovascular (Hypertension) disease care through private health facilities in Pakistan 
Cardiovascular diseases (CVDs) are one of the leading causes of death and disability in the world. Over 80% of CVD deaths take place in low-and middle-income countries. One-third of the population aged above 40 years suffers from Hypertension (HTN) and this is largely unreported as there is no registry for CVDs. No guidelines are available for use in health care facilities, especially private health facilities where practice among GPs varies considerably. We aim to conduct a Cluster Randomized Controlled trial delivering a quality HTN-CVD care package at strengthened private health facilities as compared to current practice at private health facilities.
A pragmatic cluster randomized trial, with qualitative and economic studies, will be conducted in Sargodha district of Punjab, Pakistan, from January 2012 to December 2016. At least 912 hypertensives will be registered in the two arms, six clusters per arm. The proposed cluster randomized controlled trial will evaluate the effects of delivering quality HTN-CVD care, through enabled private health care facilities, to achieve better case registration, adherence and hypertension control also blood glucose and serum cholesterol control. The trial will be conducted through the doctors and paramedics at private health facilities. Main outcomes are mean difference in Systolic blood pressure among the two arms. Secondary outcomes are mean change in total serum cholesterol levels and mean change in glycaemic control achieved in the adult hypertensive patients. Individual and Cluster level analysis will be done according to intention-to-treat.
Due to the high burden of disease where 1 in 3 individuals aged above 45 suffers from hypertension, topped with the fact that there is a dearth of a set of available, standardised guidelines for management, the disease is constantly on a hike in Pakistan. The government has made no effort to issue a set of guidelines adapted specifically for our population and this becomes more of a problem when managing CVD in urban population through private practitioners whose practices vary widely.If our set of context sensitive guidelines show an effectiveness in the proposed intervention districts it will be replicated in other such settings.
Trial registration
Current Controlled Trials ISRCTN34381594
PMCID: PMC3848995  PMID: 24066730
Cardiovascular disease; Public private mix; Urban health

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