Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen non-carcinogen model had a concordance between experimental and predicted results of 71% and the mammary carcinogen non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and estrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin, the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets.

Background

Circumcision status was examined as an independent risk factor for STIs in the HIM cohort of homosexual men in Sydney.

Methods

From 2001–2004, 1,427 initially HIV-negative men were enrolled and followed to mid-2007. All participants were offered annual STI testing. Past history of STIs was collected at baseline and information on sexual risk behaviors, every 6 months. At annual face-to-face visits, participants reported STI diagnoses made in the previous year.

Results

Circumcision was not associated with prevalent or incident HSV-1, HSV-2, or self-reported genital warts. There was also no independent association of circumcision with incident urethral gonorrhea or chlamydia. Being circumcised was associated with a significantly reduced risk of incident (HR 0.35, 95% CI 0.15–0.84), but not prevalent (OR 0.71, 95% CI 0.35–1.44) syphilis. The association was somewhat stronger among men who reported predominantly insertive unprotected anal intercourse (HR 0.10, 95% CI 0.01–0.82).

Conclusions

These are the first prospective data in homosexual men to assess circumcision status as a risk factor for STIs. Circumcised men were at reduced risk of incident syphilis but no other prevalent or incident STIs. Circumcision is unlikely to have a substantial public health impact in reducing acquisition of most STIs in homosexual men.

Background

Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study).

Methods

Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database.

Results

To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part.

Conclusions

It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.

The urokinase plasminogen activator (uPA) receptor (uPAR) is a GPI-linked cell surface protein that facilitates focused plasmin proteolytic activity at the cell surface. uPAR has been detected in macrophages infiltrating the central nervous system (CNS) and soluble uPAR has been detected in the cerebrospinal fluid during a number of CNS pathologies. However, its expression by resident microglial cells in vivo remains uncertain. In this work, we aimed to elucidate the murine CNS expression of uPAR and uPA as well as that of tissue plasminogen activator and plasminogen activator inhibitor 1 (PAI-1) during insults generating distinct and well-characterized inflammatory responses; acute intracerebral lipopolysaccharide (LPS), acute kainate-induced neurodegeneration, and chronic neurodegeneration induced by prion disease inoculation. All three insults induced marked expression of uPAR at both mRNA and protein level compared to controls (naïve, saline, or control inoculum-injected). uPAR expression was microglial in all cases. Conversely, uPA transcription and activity was only markedly increased during chronic neurodegeneration. Dissociation of uPA and uPAR levels in acute challenges is suggestive of additional proteolysis-independent roles for uPAR. PAI-1 was most highly expressed upon LPS challenge, whereas tissue plasminogen activator mRNA was constitutively present and less responsive to all insults studied. These data are novel and suggest much wider involvement of the uPAR/uPA system in CNS function and pathology than previously supposed. © 2009 Wiley-Liss, Inc.

Objective: To determine the rate of implantable cardioverter-defibrillator (ICD) implantation across the UK during the period 1998 to 2002.

Design: Observational self reporting with cross checking.

Setting: All ICD implanting centres coordinated by the National Pacemaker and ICD Database.

Patients: Every patient receiving an ICD in the UK from 1998 to 2002.

Main outcome measures: Date of implantation and postcode of each ICD recipient during the study period.

Results: ICD implantation increased in the UK in the five year period studied but fell far short of the European average and national targets. Implantation rates varied greatly by region.

Conclusions: The low rate of ICD implantation in the UK and the disparity between regions require further study to determine the barriers to this evidence based treatment.

Objective To assess whether non-polluting, more effective home heating (heat pump, wood pellet burner, flued gas) has a positive effect on the health of children with asthma.

Design Randomised controlled trial.

Setting Households in five communities in New Zealand.

Participants 409 children aged 6-12 years with doctor diagnosed asthma.

Interventions Installation of a non-polluting, more effective home heater before winter. The control group received a replacement heater at the end of the trial.

Main outcome measures The primary outcome was change in lung function (peak expiratory flow rate and forced expiratory volume in one second, FEV1). Secondary outcomes were child reported respiratory tract symptoms and daily use of preventer and reliever drugs. At the end of winter 2005 (baseline) and winter 2006 (follow-up) parents reported their child’s general health, use of health services, overall respiratory health, and housing conditions. Nitrogen dioxide levels were measured monthly for four months and temperatures in the living room and child’s bedroom were recorded hourly.

Results Improvements in lung function were not significant (difference in mean FEV1 130.7 ml, 95% confidence interval −20.3 to 281.7). Compared with children in the control group, however, children in the intervention group had 1.80 fewer days off school (95% confidence interval 0.11 to 3.13), 0.40 fewer visits to a doctor for asthma (0.11 to 0.62), and 0.25 fewer visits to a pharmacist for asthma (0.09 to 0.32). Children in the intervention group also had fewer reports of poor health (adjusted odds ratio 0.48, 95% confidence interval 0.31 to 0.74), less sleep disturbed by wheezing (0.55, 0.35 to 0.85), less dry cough at night (0.52, 0.32 to 0.83), and reduced scores for lower respiratory tract symptoms (0.77, 0.73 to 0.81) than children in the control group. The intervention was associated with a mean temperature rise in the living room of 1.10°C (95% confidence interval 0.54°C to 1.64°C) and in the child’s bedroom of 0.57°C (0.05°C to 1.08°C). Lower levels of nitrogen dioxide were measured in the living rooms of the intervention households than in those of the control households (geometric mean 8.5 μg/m3 v 15.7 μg/m3, P<0.001). A similar effect was found in the children’s bedrooms (7.3 μg/m3 v 10.9 μg/m3, P<0.001).

Conclusion Installing non-polluting, more effective heating in the homes of children with asthma did not significantly improve lung function but did significantly reduce symptoms of asthma, days off school, healthcare utilisation, and visits to a pharmacist.

Trial registration Clinical Trials NCT00489762.

Objective To determine whether insulating existing houses increases indoor temperatures and improves occupants' health and wellbeing.

Design Community based, cluster, single blinded randomised study.

Setting Seven low income communities in New Zealand.

Participants 1350 households containing 4407 participants.

Intervention Installation of a standard retrofit insulation package.

Main outcome measures Indoor temperature and relative humidity, energy consumption, self reported health, wheezing, days off school and work, visits to general practitioners, and admissions to hospital.

Results Insulation was associated with a small increase in bedroom temperatures during the winter (0.5°C) and decreased relative humidity (−2.3%), despite energy consumption in insulated houses being 81% of that in uninsulated houses. Bedroom temperatures were below 10°C for 1.7 fewer hours each day in insulated homes than in uninsulated ones. These changes were associated with reduced odds in the insulated homes of fair or poor self rated health (adjusted odds ratio 0.50, 95% confidence interval 0.38 to 0.68), self reports of wheezing in the past three months (0.57, 0.47 to 0.70), self reports of children taking a day off school (0.49, 0.31 to 0.80), and self reports of adults taking a day off work (0.62, 0.46 to 0.83). Visits to general practitioners were less often reported by occupants of insulated homes (0.73, 0.62 to 0.87). Hospital admissions for respiratory conditions were also reduced (0.53, 0.22 to 1.29), but this reduction was not statistically significant (P=0.16).

Conclusion Insulating existing houses led to a significantly warmer, drier indoor environment and resulted in improved self rated health, self reported wheezing, days off school and work, and visits to general practitioners as well as a trend for fewer hospital admissions for respiratory conditions.

This study reports the prevalence of antibodies to hepatitis B virus (HBV) and C virus (HCV), and the frequency of potential exposure to these viruses among patients and staff in six long-stay wards of a hospital caring for mentally handicapped adults from the Mersey region. A retrospective survey of risk behaviour among 134 patients and questionnaire survey of 75 nursing staff was performed. Serum samples from both groups were tested for HBV markers and patient sera for antibodies to HCV by enzyme-linked immunosorbent assay (ELISA). None of the 102 patients tested had antibodies against HCV, although 17 had detectable antibody to HBV core (anti-HBc). Seven out of the 17 were positive for HBV surface antigen. None was positive for IgM antibody to HBV core. Only 1 out of 61 staff had anti-HBc and none was positive for surface antigen. Twenty-nine of 75 (39%) staff reported bites sufficient to break the skin and 52 (69%) significant other injuries from patients; 25 (31%) of staff had not received HBV vaccination. None of the patients had received HBV vaccine. We conclude that HCV does not appear to be a major hazard in this closed community but the prevalence of HBV markers indicating past exposure among patients is high, vaccine uptake is incomplete and incidents which may allow viral transmission are frequent.

We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 × 10−13 and 7.7 × 10−9, respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.

Though Pleistocene refugia are frequently cited as drivers of species diversification, comparisons of molecular divergence among sister species typically indicate a continuum of divergence times from the Late Miocene, rather than a clear pulse of speciation events at the Last Glacial Maximum. Community-scale inference methods that explicitly test for multiple vicariance events, and account for differences in ancestral effective population size and gene flow, are well suited for detecting heterogeneity of species' responses to past climate fluctuations. We apply this approach to multi-locus sequence data from five co-distributed frog species endemic to the Wet Tropics rainforests of northeast Australia. Our results demonstrate at least two episodes of vicariance owing to climate-driven forest contractions: one in the Early Pleistocene and the other considerably older. Understanding how repeated cycles of rainforest contraction and expansion differentially affected lineage divergence among co-distributed species provides a framework for identifying evolutionary processes that underlie population divergence and speciation.

Craniofacial disorders are one of the most common category of birth defects worldwide, and are an important topic of biomedical research. In order to better understand these disorders and correlate them with genetic patterns and life outcomes, researchers need to quantify the craniofacial anatomy. In this paper we introduce several different craniofacial descriptors that are being used in research studies for two craniofacial disorders: the 22q11.2 deletion syndrome (a genetic disorder) and plagiocephaly/brachycephaly, disorders caused by pressure on the head. Experimental results show that our descriptors show promise for quantifying craniofacial shape.

Although use of buprenorphine in the treatment of opioid dependence is expected to continue to increase, little is known about the optimal setting for providing the medical and psychosocial care required with buprenorphine pharmacotherapy.

OBJECTIVE

This study compared buprenorphine therapy delivered in three distinct treatment settings: an opioid-treatment program (OTP) offering individual counseling; a group counseling program utilizing the manualized Matrix Model (MMM) of cognitive-behavioral treatment; and a private clinic setting mirroring standard medical management for buprenorphine treatment provided specifically at a psychiatrist’s private practice (PCS).

METHOD

Participants were inducted on buprenorphine and provided with treatment over a 52-week study duration. All participants were scheduled for weekly treatment visits for the first 6 study weeks, and two sites reduced treatment to monthly visits for dispensing of medication and psychosocial counseling. Outcomes include opioid use, participant retention in treatment, and treatment participation.

RESULTS

Participants presenting for treatment at the sites differed only by race/ethnicity, and opioid use did not differ by site. Retention differed by treatment site, with the number of participants who stayed in the study until the end of 20 weeks significantly associated with treatment site. The mean number of minutes spent in each individual counseling session also differed by site. Although no difference in opioid use by treatment site was found, results document a significant association between opioid use and buprenorphine dose.

DISCUSSION

These results show some differences by treatment site, although the similarity and relative ease in which the sites were able to recruit participants for treatment with buprenorphine, and minor implementation problems reported suggests the feasibility of treatment with buprenorphine across various treatment settings.

CONCLUSION

Similar rates of continued opioid use across study sites and few qualitative reports of problems indicates that treatment with buprenorphine and associated psychosocial counseling are safe and relatively easy to implement in a variety of treatment settings.

Background

Although many global health programs focus on providing clinical care or medical education, improving clinical operations can have a significant effect on patient care delivery, especially in developing health systems without high-level operations management. Lean manufacturing techniques have been effective in decreasing emergency department (ED) length of stay, patient waiting times, numbers of patients leaving without being seen, and door-to-balloon times for ST-elevation myocardial infarction in developed health systems; but use of Lean in low to middle income countries with developing emergency medicine systems has not been well characterized.

Objectives

To describe the application of Lean manufacturing techniques to improve clinical operations at Komfo Anokye Teaching Hospital in Ghana and to identify key lessons learned to aid future global EM initiatives.

Methods

A three-week Lean improvement program focused on the hospital admissions process at Komfo Anokye Teaching Hospital was completed by a 14-person team in six stages: problem definition, scope of project planning, value stream mapping, root cause analysis, future state planning, and implementation planning.

Results

The authors identified eight lessons learned during our use of Lean to optimize the operations of an ED in a global health setting: 1) the Lean process aided in building a partnership with Ghanaian colleagues; 2) obtaining and maintaining senior institutional support is necessary and challenging; 3) addressing power differences among the team to obtain feedback from all team members is critical to successful Lean analysis; 4) choosing a manageable initial project is critical to influence long-term Lean use in a new environment; 5) data intensive Lean tools can be adapted and are effective in a less resourced health system; 6) several Lean tools focused on team problem solving techniques worked well in a low resource system without modification; 7) using Lean highlighted that important changes do not require an influx of resources; 8) despite different levels of resources, root causes of system inefficiencies are often similar across health care systems, but require unique solutions appropriate to the clinical setting.

Conclusions

Lean manufacturing techniques can be successfully adapted for use in developing health systems. Lessons learned from this Lean project will aid future introduction of advanced operations management techniques in low to middle income countries.

Chronic Obstructive Pulmonary Disease (COPD) is a strong risk factor for lung cancer. Published studies regarding variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive.

We evaluated 470 single nucleotide polymorphisms (SNPs) from 56 genes of these 3 pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established.

Twenty-one SNPs were found to be significantly associated with risk of COPD (P<0.01); gene-based analyses confirmed 2 genes (GCLC and GSS) and identified 3 additional (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; 8 SNPs altered COPD risk with lung cancer 3.1-fold, and 4 SNPs altered the risk without lung cancer 2.3-fold.

Our findings indicate that multiple genetic variations in the 3 selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both.

An on-plate testing method using formic acid was evaluated on the Bruker Biotyper matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry system using 90 yeast and 78 Corynebacterium species isolates, and 95.6 and 81.1% of yeast and 96.1 and 92.3% of Corynebacterium isolates were correctly identified to the genus and species levels, respectively. The on-plate method using formic acid yielded identification percentages similar to those for the conventional but more laborious tube-based extraction.

DNA sequence context has long been known to modulate detection and repair of DNA damage. Recent studies using experimental and computational approaches have sought to provide a basis for this observation. We have previously shown that an α-anomeric adenosine (αA) flanked by cytosines (5′CαAC-3′) resulted in a kinked DNA duplex with an enlarged minor groove. Comparison of different flanking sequences revealed that a DNA duplex containing a 5′CαAG-3′ motif exhibits unique substrate properties. However, this substrate was not distinguished by unusual thermodynamic properties. To understand the structural basis of the altered recognition, we have determined the solution structure of a DNA duplex with a 5′CαAG-3′ core, using an extensive set of restraints including dipolar couplings and backbone torsion angles. The NMR structure exhibits an excellent agreement with the data (total RX <5.3%). The αA base is intrahelical, in a reverse Watson–Crick orientation, and forms a weak base pair with a thymine of the opposite strand. In comparison to the DNA duplex with a 5′CαAC-3′ core, we observe a significant reduction of the local perturbation (backbone, stacking, tilt, roll, and twist), resulting in a straighter DNA with narrower minor groove. Overall, these features result in a less perturbed DNA helix and obscure the presence of the lesion compared to the 5′CαAC-3′ sequence. The improved stacking of the 5′CαAG-3′ core also affects the energetics of the DNA deformation that is required to form a catalytically competent complex. These traits provide a rationale for the modulation of the recognition by endonuclease IV.

Introduction

Routine palliative bypass has been advocated for palliation of patients with pancreatic adenocarcinoma who have inoperable disease discovered at the time of surgery. We examined trends in the relative use of palliative bypass over time with an emphasis on identifying changes in surgical indications, type of bypass performed, as well as perioperative outcomes associated with surgical palliation.

Methods

Between 1996 and 2010, 1,913 patients with pancreatic adenocarcinoma in the head of the pancreas were surgically explored. Data regarding preoperative symptoms, intraoperative findings, type of surgical procedure performed, as well as perioperative and long-term outcomes were collected and analyzed.

Results

Of the 1,913 patients, 583 (30.5%) underwent a palliative procedure. Most patients presented with jaundice (72.2%). The majority of patients were evaluated by CT scan (97.4%), which revealed a median tumor size of 3.2 cm. Most patients who underwent surgical palliation (64.5%) had a double bypass, while a minority had either gastrojejunostomy (28.2%) or hepaticojejunostomy (7.2%) alone. While the number of pancreaticoduodenectomies remained relatively stable over time, there was a temporal decrease in the utilization of palliative bypass (P<0.001). Unanticipated locally advanced disease vs. liver/peritoneal metastasis as the indication for palliative surgery also changed over time (1996–2001: 47.8% vs. 52.2%; 2002–2007: 49.2% vs. 50.8%; 2008–2010: 17.2% vs. 82.7%) (P = 0.005). Palliative failure rates were 2.3% after hepaticojejunostomy and 3.1% after grastrojejunostomy. Patients with unsuspected metastatic disease had a worse survival compared with patients who had locally unresectable disease (median survival: 5 vs. 8 months, respectively; HR = 1.43, P = 0.001).

Conclusion

Palliative bypass procedures were less frequently performed over time, probably due to a significant decrease in the rate of unanticipated advanced locoregional disease at the time of exploration. While palliative bypass was effective, survival in the setting of metastatic disease was extremely short.

Aims

Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D.

Methods

12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15null macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass.

Results

12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15null mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass.

Conclusions

These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.

Background

Clinically important medication errors are common after hospital discharge. They include preventable or ameliorable adverse drug events as well as medication discrepancies or non-adherence with high potential for future harm (potential adverse drug events).

Objective

The Pharmacist Intervention for Low Literacy in Cardiovascular Disease (PILL-CVD) study sought to determine the effect of a tailored intervention on the occurrence of clinically important medication errors after hospital discharge.

Design

Randomized controlled trial with concealed allocation and blinded outcome assessors.

Setting

Two tertiary care academic hospitals.

Patients

Adults hospitalized with acute coronary syndromes or acute decompensated heart failure.

Intervention

Pharmacist-assisted medication reconciliation, inpatient pharmacist counseling, low-literacy adherence aids, and individualized telephone follow-up after discharge.

Measurements

The primary outcome was the number of clinically important medication errors per patient during the first 30 days after hospital discharge. Secondary outcomes included preventable or ameliorable adverse drug events, as well as potential adverse drug events.

Results

Among 851 participants, 432 (50.8%) experienced 1 or more clinically important medication errors; 23% of such errors were judged to be serious, and 2% life-threatening. Adverse drug events occurred in 258 patients (30.3%) and potential adverse drug events in 253 (29.7%). The intervention did not significantly alter the per-patient number of clinically important medication errors (IRR=0.92; 95% CI, 0.77 to 1.10) or adverse drug events (IRR=1.09; CI, 0.86 to 1.39). Intervention patients tended to have fewer potential adverse drug events (IRR=0.80; CI, 0.61 to 1.04).

Limitations

The characteristics of the study hospitals and participants may limit generalizability.

Conclusions

Clinically important medication errors were present among half of patients after hospital discharge and were not significantly reduced by a health-literacy sensitive, pharmacist-delivered intervention.

Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.

Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.

A putative driver of global amphibian decline is the panzootic chytrid fungus Batrachochytrium dendrobatidis (Bd). While Bd has been documented across continental Africa, its distribution in West Africa remains ambiguous. We tested 793 West African amphibians (one caecilian and 61 anuran species) for the presence of Bd. The samples originated from seven West African countries - Bénin, Burkina Faso, Côte d'Ivoire, Ghana, Guinea, Liberia, Sierra Leone - and were collected from a variety of habitats, ranging from lowland rainforests to montane forests, montane grasslands to humid and dry lowland savannahs. The species investigated comprised various life-history strategies, but we focused particularly on aquatic and riparian species. We used diagnostic PCR to screen 656 specimen swabs and histology to analyse 137 specimen toe tips. All samples tested negative for Bd, including a widespread habitat generalist Hoplobatrachus occipitalis which is intensively traded on the West African food market and thus could be a potential dispersal agent for Bd. Continental fine-grained (30 arc seconds) environmental niche models suggest that Bd should have a broad distribution across West Africa that includes most of the regions and habitats that we surveyed. The surprising apparent absence of Bd in West Africa indicates that the Dahomey Gap may have acted as a natural barrier. Herein we highlight the importance of this Bd-free region of the African continent - especially for the long-term conservation of several threatened species depending on fast flowing forest streams (Conraua alleni (“Vulnerable”) and Petropedetes natator (“Near Threatened”)) as well as the “Critically Endangered” viviparous toad endemic to the montane grasslands of Mount Nimba (Nimbaphrynoides occidentalis).

Objectives. To evaluate hospital and outpatient pharmacists’ pharmacogenomics knowledge before and 2 months after participating in a targeted, case-based pharmacogenomics continuing education program.

Design. As part of a continuing education program accredited by the Accreditation Council for Pharmacy Education (ACPE), pharmacists were provided with a fundamental pharmacogenomics education program.

Evaluation. An 11-question, multiple-choice, electronic survey instrument was distributed to 272 eligible pharmacists at a single campus of a large, academic healthcare system. Pharmacists improved their pharmacogenomics test scores by 0.7 questions (pretest average 46%; posttest average 53%, p=0.0003).

Conclusions. Although pharmacists demonstrated improvement, overall retention of educational goals and objectives was marginal. These results suggest that the complex topic of pharmacogenomics requires a large educational effort in order to increase pharmacists’ knowledge and comfort level with this emerging therapeutic opportunity.

This software article describes the GATE family of open source text analysis tools and processes. GATE is one of the most widely used systems of its type with yearly download rates of tens of thousands and many active users in both academic and industrial contexts. In this paper we report three examples of GATE-based systems operating in the life sciences and in medicine. First, in genome-wide association studies which have contributed to discovery of a head and neck cancer mutation association. Second, medical records analysis which has significantly increased the statistical power of treatment/outcome models in the UK's largest psychiatric patient cohort. Third, richer constructs in drug-related searching. We also explore the ways in which the GATE family supports the various stages of the lifecycle present in our examples. We conclude that the deployment of text mining for document abstraction or rich search and navigation is best thought of as a process, and that with the right computational tools and data collection strategies this process can be made defined and repeatable. The GATE research programme is now 20 years old and has grown from its roots as a specialist development tool for text processing to become a rather comprehensive ecosystem, bringing together software developers, language engineers and research staff from diverse fields. GATE now has a strong claim to cover a uniquely wide range of the lifecycle of text analysis systems. It forms a focal point for the integration and reuse of advances that have been made by many people (the majority outside of the authors' own group) who work in text processing for biomedicine and other areas. GATE is available online <1> under GNU open source licences and runs on all major operating systems. Support is available from an active user and developer community and also on a commercial basis.