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1.  The impact of translocations on neutral and functional genetic diversity within and among populations of the Seychelles warbler 
Molecular Ecology  2014;23(9):2165-2177.
Translocations are an increasingly common tool in conservation. The maintenance of genetic diversity through translocation is critical for both the short- and long-term persistence of populations and species. However, the relative spatio-temporal impacts of translocations on neutral and functional genetic diversity, and how this affects genetic structure among the conserved populations overall, have received little investigation. We compared the impact of translocating different numbers of founders on both microsatellite and major histocompatibility complex (MHC) class I diversity over a 23-year period in the Seychelles warbler (Acrocephalus sechellensis). We found low and stable microsatellite and MHC diversity in the source population and evidence for only a limited loss of either type of diversity in the four new populations. However, we found evidence of significant, but low to moderate, genetic differentiation between populations, with those populations established with fewer founders clustering separately. Stochastic genetic capture (as opposed to subsequent drift) was the main determinant of translocated population diversity. Furthermore, a strong correlation between microsatellite and MHC differentiation suggested that neutral processes outweighed selection in shaping MHC diversity in the new populations. These data provide important insights into how to optimize the use of translocation as a conservation tool.
PMCID: PMC4237152  PMID: 24689851
conservation; differentiation; drift; genetic capture; genetic diversity; major histocompatibility complex; re-introduction
2.  Analysis of Feature Intervisibility and Cumulative Visibility Using GIS, Bayesian and Spatial Statistics: A Study from the Mandara Mountains, Northern Cameroon 
PLoS ONE  2014;9(11):e112191.
The locations of diy-geδ-bay (DGB) sites in the Mandara Mountains, northern Cameroon are hypothesized to occur as a function of their ability to see and be seen from points on the surrounding landscape. A series of geostatistical, two-way and Bayesian logistic regression analyses were performed to test two hypotheses related to the intervisibility of the sites to one another and their visual prominence on the landscape. We determine that the intervisibility of the sites to one another is highly statistically significant when compared to 10 stratified-random permutations of DGB sites. Bayesian logistic regression additionally demonstrates that the visibility of the sites to points on the surrounding landscape is statistically significant. The location of sites appears to have also been selected on the basis of lower slope than random permutations of sites. Using statistical measures, many of which are not commonly employed in archaeological research, to evaluate aspects of visibility on the landscape, we conclude that the placement of DGB sites improved their conspicuousness for enhanced ritual, social cooperation and/or competition purposes.
PMCID: PMC4226507  PMID: 25383883
3.  Restless Legs Syndrome, pica, and iron status in blood donors 
Transfusion  2013;53(8):1645-1652.
The association of blood donation related iron deficiency with pica or Restless Leg Syndrome (RLS) remains poorly elucidated. This study evaluated the prevalence of RLS and pica in blood donors completing the REDS-II Iron Status Evaluation (RISE) Study.
RISE enrolled 2425 blood donors in a prospective cohort study; 1334 donors provided blood samples to characterize iron status and answered a questionnaire inquiring into symptoms of RLS and pica at a final visit after 15–24 months of follow-up. Associations between both conditions and iron status were evaluated.
There were 9% and 20% of donors reporting symptoms of Probable or Probable/Possible RLS, respectively. Iron depletion and donation intensity were not predictive of RLS. Pica was reported by 65 donors (5.5%), half of whom reported daily cravings. Prevalence of pica increased with degree of iron depletion in women (2% in iron replete females, 13% in those with ferritin < 12ng/mL), but not in men. Probable RLS and pica co-expressed in 8 individuals, but no more frequently than expected by chance.
RLS and pica have been associated with iron deficiency in non-donor populations. This study indicates a potentially high prevalence of RLS in frequent blood donors but shows no association with iron status or donation intensity. Low iron stores were associated with higher prevalence of pica, but only in females. Furthermore, the results are incompatible with RLS and pica sharing a common pathophysiology.
PMCID: PMC4226336  PMID: 23763445
blood donor; iron depletion; donation interval; pica; Restless Legs Syndrome
4.  Laboratory variables for assessing iron deficiency in REDS-II Iron Status Evaluation (RISE) blood donors 
Transfusion  2013;53(11):2766-2775.
Iron deficiency is common in regular blood donors. We evaluated the diagnostic sensitivity and specificity of red blood cell (RBC) hematology analyzer indices to assess iron status as a part of donor management.
A total of 1659 male and female donors from the Retrovirus Epidemiology Donor Study-II (REDS-II) Donor Iron Status Evaluation (RISE) study who were either first-time/reactivated (FT/ RA; no donations for 2 years) or frequent donors were recruited into a longitudinal study of regular donation of RBCs. Of these, 1002 donors returned 15 to 24 months later for a final assessment. Absent iron stores (AIS) was defined as plasma ferritin level of less than 12 µ.g/L. Logarithm of the ratio of soluble transferrin receptor to ferritin of at least 2.07 (≥97.5% in FT/RA males) was used to define iron-deficient erythropoiesis (IDE). Receiver operating characteristics analysis was performed to assess selected RBC indices (e.g., percentage of hypochromic mature RBCs, proportion of hypochromic mature RBCs [HYPOm], and hemoglobin [Hb] content of reticulocytes [CHr]) in identifying AIS and IDE.
HYPOm and CHr detected IDE with comparable sensitivity, 72% versus 69%, but differed in specificity: HYPOm 68% and CHr 53%. For detecting AIS, sensitivity was improved to 85% for HYPOm and 81% for CHr but specificity was reduced for both. Venous Hb had high specificity but poor sensitivity for IDE and AIS. A plasma ferritin level of less than 26.7 u.g/L was a good surrogate for assessing IDE.
RBC indices correlate with AIS and IDE and are more informative than Hb measurement, but lack sufficient sensitivity and specificity to be used as diagnostic tools in blood donors at risk for iron deficiency.
PMCID: PMC3895107  PMID: 23617531
5.  Museum DNA reveals the demographic history of the endangered Seychelles warbler 
Evolutionary Applications  2014;7(9):1134-1143.
The importance of evolutionary conservation – how understanding evolutionary forces can help guide conservation decisions – is widely recognized. However, the historical demography of many endangered species is unknown, despite the fact that this can have important implications for contemporary ecological processes and for extinction risk. Here, we reconstruct the population history of the Seychelles warbler (Acrocephalus sechellensis) – an ecological model species. By the 1960s, this species was on the brink of extinction, but its previous history is unknown. We used DNA samples from contemporary and museum specimens spanning 140 years to reconstruct bottleneck history. We found a 25% reduction in genetic diversity between museum and contemporary populations, and strong genetic structure. Simulations indicate that the Seychelles warbler was bottlenecked from a large population, with an ancestral Ne of several thousands falling to <50 within the last century. Such a rapid decline, due to anthropogenic factors, has important implications for extinction risk in the Seychelles warbler, and our results will inform conservation practices. Reconstructing the population history of this species also allows us to better understand patterns of genetic diversity, inbreeding and promiscuity in the contemporary populations. Our approaches can be applied across species to test ecological hypotheses and inform conservation.
PMCID: PMC4231601  PMID: 25553073
Acrocephalus sechellensis; approximate Bayesian computation; bird; bottleneck; island; microsatellite
6.  Design, Synthesis and Characterization of Nucleic Acid-Functionalized Gold Surfaces for Biomarker Detection 
Nucleic acid-functionalized gold surfaces have been used extensively for the development of biological sensors. The development of an effective biomarker detection assay requires careful design, synthesis and characterization of probe components. In this feature article, we describe fundamental probe development constraints and provide a critical appraisal of the current methodologies and applications in the field. We discuss critical issues and obstacles that impede the sensitivity and reliability of the sensors to underscore the challenges that must be met to advance the field of biomarker detection.
PMCID: PMC4211628  PMID: 21905721
Gold nanoparticles; nucleic acid sensors; hAuNPs; electrochemistry; biobarcode assay; aptamers; DNAzymes
7.  Detection of Respiratory Syncytial Virus Using Nanoparticle Amplified Immuno-PCR 
Analytical biochemistry  2010;410(1):141-148.
In traditional immuno-PCR a single antibody recognition event is associated with one to three DNA tags, which are subsequently amplified by PCR. Here, we describe a nanoparticle amplified immuno-PCR (NPA-IPCR) assay that combines antibody recognition of ELISA with a 50-fold nanoparticle valence amplification step prior to tag amplification by PCR. The assay detects a respiratory syncytial virus (RSV) surface protein using an antibody bound to a 15 nm gold nanoparticle co-functionalized with thiolated DNA complementary to a hybridized to 76-base tag DNA with a tag DNA to antibody ratio of 50 to 1. The presence of virus particles triggers the formation of a “sandwich” complex comprised of the gold nanoparticle construct, virus and an antibody functionalized magnetic particle used for extraction. After extraction, DNA tags are released by heating to 95°C and detected via real-time PCR. The limit of detection of the assay was compared to ELISA and RT-PCR using RSV infected HEp-2 cell extracts. NPA-IPCR showed a ~4000-fold improvement in the limit of detection compared to ELISA and a 4-fold improvement compared to viral RNA extraction followed by traditional RTPCR. NPA-IPCR offers a viable platform for the development of an early-stage diagnostics requiring an exceptionally low limit of detection.
PMCID: PMC4208676  PMID: 21111702
Immuno-PCR; PCR; Viral Detection; Respiratory Syncytial Virus; Gold Nanoparticle; Magnetic Extraction
8.  Comparative Analysis of Gene Expression Changes Mediated by Individual Constituents of Hemozoin 
Chemical research in toxicology  2009;22(3):433-445.
Plasmodium protozoa, the source of malarial infections, catabolize large quantities of hemoglobin during an intra-erythrocytic phase. During this process, free heme is detoxified through biomineralization into an insoluble heme aggregate, hemozoin (Hz). In its native state, Hz is associated with a variety of lipid peroxidation products including 4-hydroxy-2-nonenal (HNE). In the present study, gene expression profiles were used to compare responses to two of the individual components of Hz in a model macrophage cell line. LPS-stimulated RAW 264.7 cells were exposed to HNE and the synthetic form of Hz, β-hematin (BH), for 6 or 24 h. Microarray analysis identified alterations in gene expression induced by exposure to HNE and opsonized BH (fold change ≥1.8, p-value ≤0.01). Patterns of gene expression were compared to changes induced by an opsonized control latex bead challenge in LPS-stimulated cells and revealed that the BH response was predominantly phagocytic. Ingenuity Pathway Analysis demonstrated that HNE mediated a short term oxidative stress response and had a prolonged effect on the expression of genes associated with categories of ‘Cell Cycle’, ‘Cellular Assembly and Organization’, ‘DNA Replication, Recombination, and Repair’, and ‘Cellular Development’. Comparisons of expression changes caused by BH and HNE with those observed during malarial infection suggest that BH and HNE are involved in inflammatory response modulation, altered NF-κB signal transduction, extracellular matrix (ECM) degradation, and dyserythropoiesis. HNE exposure led to several significant steady-state expression changes including repressed chemokine (C-C motif) ligand 5 (Ccl5) indicative of dyserythropoiesis, and a severe matrix metalloproteinase 9 (Mmp9)/tissue inhibitor of metalloproteinase 1 (Timp1) imbalance in favor of ECM proteolysis.
PMCID: PMC4208677  PMID: 19191707
9.  Enrollment in Research Under Exception from Informed Consent: The Patients' Experiences in Emergency Research (PEER) Study 
Resuscitation  2013;84(10):1416-1421.
Resuscitation research requires an exception from informed consent (EFIC). Despite concerns that patients may find EFIC unacceptable, the views and experiences of patients enrolled in an EFIC study are largely unknown.
The Patients' Experience in Emergency Research (PEER) Study was nested within the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) for pre-hospital treatment of status epilepticus. PEER included 61 EFIC enrollees or their surrogates from 5 sites. Interviews used a structured, interactive guide focusing on acceptance of EFIC enrollment in RAMPART and existing regulatory protections. Simple statistics were generated, and textual data were analyzed for common themes.
24 enrolled patients and 37 surrogates were successfully interviewed. 49/60 (82%) were glad they or their family member were included in RAMPART; 54/57 (95%) felt research on emergency seizure treatment is important. 43/59 (73%) found their inclusion under EFIC acceptable;10 (17%) found it unacceptable, and 6 (10%) were neutral. There were no statistically significant interactions between enrollment attitudes and demographic characteristics, though there were trends toward lower acceptance among interviewees who were non-white, less educated, or had prior research experience. The most common concerns related to lack of consent prior to RAMPART enrollment. Positive responses related to perceived medical benefits, recognition of the impracticality of consent, and wanting doctors to do what needs to be done in emergencies. Many participants had difficulty understanding the trial and EFIC.
Most subjects had positive views of enrollment, and acceptance generally correlated with results of community consultation studies.
PMCID: PMC3770787  PMID: 23603291
10.  An Analysis of Risk Factors for HIV Infection among Chinese Blood Donors 
Transfusion  2013;53(0 0):2431-2440.
Information regarding the risk factors for HIV infection among Chinese donors is important for understanding the trend of HIV transmission routes and for developing effective donor behavioral screening policies.
In 2009–2011, 77 HIV positive and 649 HIV negative consented donors who screened non-reactive for HBV, HCV, Syphilis, and ALT in four REDS-II Chinese regions received and completed a questionnaire by mail regarding their recent and past medical procedures, drug use, and sexual behaviors as well as the reason for making a donation. Exploratory and confirmatory factor analyses grouped questions into three risk factors. Multivariable logistic regression analysis examined the relationship between dichotomized factor scores (> median for higher risks vs. <=median for lower risks) and HIV status adjusting for center, age, gender, and education.
More males (81% vs. 64%), donors with < high school education (38.2% vs. 15.5%), and divorced/separated/widowed donors (14% vs. 4%) were in the HIV positive than negative group. The three risk factors were: Test-seeking tendency, medical-related risks, and behavioral risks. In multivariable logistic regression analysis, greater test-seeking tendency and behavioral risks were associated with HIV infection, adjusted ORs being 2.2 (1.2–4.1) and 3.8 (1.8–7.9) respectively; but medical risks were not, OR: 1.2 (0.6–2.2). In comparison to less high school education, high school and above education was significantly associated with lower risks for HIV infection, ORs being 0.35 (CI: 0.17–0.70) and 0.17 (CI: 0.09–0.33), respectively.
Test-seeking tendency and high-risk sexual behaviors are important predictors of HIV infection in Chinese blood donors, suggesting that the Health History Inquiry used in donor selection process needs improvement to defer high-risk donors more effectively.
PMCID: PMC3626745  PMID: 23305132
risk factors for HIV infection; Chinese Blood donors; behavioral risks; medical risks; test-seeking and HIV infection
11.  The potential impact of selective donor deferrals based on estimated blood volume on vasovagal reactions and donor deferral rates 
Transfusion  2010;50(6):1265-1275.
Whole blood donation in the United States is restricted in volume to 10.5 mL/kg or less in an effort to prevent hypovolemic reactions, but still may exceed more than 15% of a donor’s estimated blood volume (EBV). We analyzed the association of EBV with prefaint and systemic vasovagal reactions (SVRs) among whole blood donors and the potential impact of an EBV-based deferral policy.
Independent predictors for prefaint reactions and SVRs were assessed by multivariate logistic regression analysis on 591,177 unique donors participating in the Retrovirus Epidemiology Donor Study-II study.
Young age (16 years old odds ratio [OR], 3.70; 95% confidence interval [CI], 2.78-4.94), low EBV (<3.5 L OR, 3.30; 95% CI, 2.57-4.23), and first-time donation status (OR, 2.33; 95% CI, 2.03-2.67) were the strongest predictors for SVRs, with similar trends seen for prefaint reactions. Sex, height, race, blood center, and donation site were weakly associated predictors. A total of 5.6% of all donors had an EBV of less than 3.5 L and experienced 12.5% of all prefaint reactions and 14.5% of SVRs. The highest reaction rates were seen in donors less than 23 years old with an EBV of less than 3.5 L who comprised 2.7% of all donors, who were mostly female (99.9%), and who experienced 8.8% of prefaint reactions and 11.0% of SVRs.
Young age, low EBV, and first-time donation status are the major correlates of prefaint reactions and SVRs, suggesting that high school and college donors are at particular risk. Deferral of donors with low EBV who are less than 23 years old may offer a rational approach to protecting donors at greater risk of reactions without jeopardizing the adequacy of the blood supply.
PMCID: PMC4167765  PMID: 20113451
12.  Identification of β-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity 
Graphical abstract
•Hemozoin formation is a prime drug target pathway to probe for new lead compounds.•We examined the VICB library of compounds for in vitro β-hematin inhibition.•β-Hematin inhibitors were tested for in vitro antimalarial activity in two P. falciparum strains.•Chemical scaffolds with target-specific and in vitro antimalarial activity were identified.
The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though in vivo formation of hemozoin occurs within the presence of neutral lipids, the lipophilic detergent NP-40 was previously shown to serve as a surrogate in the β-hematin (synthetic hemozoin) formation process. Consequently, an NP-40 mediated β-hematin formation assay was developed for use in high-throughput screening. Here, the assay was utilized to screen 144,330 compounds for the identification of inhibitors of crystallization, resulting in 530 hits. To establish the effectiveness of these target-based β-hematin inhibitors against Plasmodiumfalciparum, each hit was further tested in cultures of parasitized red blood cells. This effort revealed that 171 of the β-hematin inhibitors are also active against the parasite. Dose–response data identified 73 of these β-hematin inhibitors have IC50 values ⩽5 μM, including 25 compounds with nanomolar activity against P. falciparum. A scaffold-based analysis of this data identified 14 primary scaffolds that represent 46% of the 530 total hits. Representative compounds from each of the classes were further assessed for hemozoin inhibitory activity in P. falciparum infected human erythrocytes. Each of the hit compounds tested were found to be positive inhibitors, while a negative control did not perturb this biological pathway in culture.
PMCID: PMC4266794  PMID: 25516843
Plasmodium falciparum; Malaria; Hemozoin; β-Haematin; High-throughput screen; Scaffolds
13.  Adiponectin is not required for exercise training‐induced improvements in glucose and insulin tolerance in mice 
Physiological Reports  2014;2(9):e12146.
Adiponectin (Ad) is a potent insulin‐sensitizing adipokine that has been found to activate pathways involved in the adaptation to exercise. Therefore, we examined whether Ad is required for the increased insulin response observed following exercise training in Ad knockout mice (AdKO). Eight weeks of exercise training significantly increased glucose and insulin tolerance in both wild type (WT) and AdKO mice. There were no differences in glucose tolerance between genotypes but insulin tolerance was improved to a greater extent in AdKO compared to WT mice following exercise training (+26%, P < 0.05). There were no genotype differences in the insulin‐stimulated phosphorylation of AKT or AS160 in red or white gastrocnemius muscle (RG, WG). Exercise training increased total AKT and AS160 protein content in RG and total AS160 protein content in WG. There were no genotype differences in total AKT or AS160. However, exercise training induced a more robust increase in total AS160 in RG from AdKO (+44 ± 8%, P < 0.05) compared to WT mice (+28 ± 7%, P = 0.06). There were no differences in total GLUT4 or FAT/CD36 in RG or WG in WT or AdKO, with or without exercise training. Similarly, there were no differences in RER, VO2, or activity between any groups. Our results indicate the presence of Ad is not required for exercise‐induced increases in insulin response. Furthermore, it appears that exercise may improve insulin sensitivity to a greater extent in the absence of Ad, suggesting the presence of an unknown compensatory mechanism.
Collectively, our results demonstrate that the absence of Ad does not impair the capacity of endurance exercise training to increase glucose and insulin tolerance in AdKO mice. In addition, there were no impairments in insulin signaling or in the protein content of AKT or AS160. Taken together with previous findings, our data indicate that AdKO mice may have sufficient compensations to override the absence of Ad.
PMCID: PMC4270243  PMID: 25214523
Adiponectin; adiponectin knockout mice; exercise training; glucose and insulin tolerance; insulin response; skeletal muscle
14.  Does Rh Immune Globulin Suppress HLA Sensitization in Pregnancy? 
Transfusion  2012;53(9):2069-2077.
How Rh immune globulin (RhIG) prevents sensitization to D antigen is unclear. If RhIG Fc delivers a nonspecific immunosuppressive signal, then RhIG may inhibit sensitization to antigens other than D. HLA antibody prevalence was compared in previously pregnant RhD negative versus RhD positive women to investigate whether RhIG suppresses HLA sensitization.
In the Leukocyte Antibody Prevalence Study (LAPS)1, 7,920 volunteer blood donors were screened for anti-HLA antibodies and surveyed about prior pregnancies and transfusions. A secondary analysis of the LAPS database was performed.
RhD negative women ≤40 years old (presumed to have received antenatal ± postpartum RhIG in all pregnancies) had a significantly lower HLA sensitization rate than RhD positive women (RR 0.58, 95% CI 0.40–0.83). When stratified by deliveries (1, 2, 3, or ≥4), RhD negative women ≤40 were HLA sensitized less often than RhD positive women in every case. In contrast, a clear relationship between RhD type and HLA sensitization was not seen in older previously pregnant women whose childbearing years are presumed to have preceded the use of routine RhIG prophylaxis. In a multivariable logistic regression model, RhD negative women ≤40 years old remained significantly less likely to be HLA sensitized compared with RhD positive women after adjusting for parity, time from last pregnancy, lost pregnancies, and transfusions (OR 0.55, 95% CI 0.34–0.88).
Consistent with a nonspecific immunosuppressive effect of RhIG, younger previously pregnant RhD negative women were less likely than previously pregnant RhD positive women to be HLA sensitized.
PMCID: PMC3609922  PMID: 23252646
Rh immune globulin (RhIG); HLA sensitization
15.  Treating an Established Episode of Delirium in Palliative Care: Expert Opinion and Review of the Current Evidence Base With Recommendations for Future Development 
Delirium is a highly prevalent complication in patients in palliative care settings, especially in the end-of-life context.
To review the current evidence base for treating episodes of delirium in palliative care settings and propose a framework for future development.
We combined multidisciplinary input from delirium researchers and other purposely selected stakeholders at an international delirium study planning meeting. This was supplemented by a literature search of multiple databases and relevant reference lists to identify studies regarding therapeutic interventions for delirium.
The context of delirium management in palliative care is highly variable. The standard management of a delirium episode includes the investigation of precipitating and aggravating factors followed by symptomatic treatment with drug therapy. However, the intensity of this management depends on illness trajectory and goals of care in addition to the local availability of both investigative modalities and therapeutic interventions. Pharmacologically, haloperidol remains the practice standard by consensus for symptomatic control. Dosing schedules are derived from expert opinion and various clinical practice guidelines as evidence-based data from palliative care settings are limited. The commonly used pharmacologic interventions for delirium in this population warrant evaluation in clinical trials to examine dosing and titration regimens, different routes of administration, and safety and efficacy compared with placebo.
Delirium treatment is multidimensional and includes the identification of precipitating and aggravating factors. For symptomatic management, haloperidol remains the practice standard. Further high-quality collaborative research investigating the appropriate treatment of this complex syndrome is needed.
PMCID: PMC4081457  PMID: 24480529
Delirium; palliative care; evidence-based medicine; therapeutics; decision making; hospices
16.  Clinical Practice Guidelines for Delirium Management: Potential Application in Palliative Care 
Delirium occurs in patients across a wide array of health care settings. The extent to which formal management guidelines exist or are adaptable to palliative care is unclear.
This review aims to 1) source published delirium management guidelines with potential relevance to palliative care settings, 2) discuss the process of guideline development, 3) appraise their clinical utility, and 4) outline the processes of their implementation and evaluation and make recommendations for future guideline development.
We searched PubMed (1990–2013), Scopus, U.S. National Guideline Clearinghouse, Google, and relevant reference lists to identify published guidelines for the management of delirium. This was supplemented with multidisciplinary input from delirium researchers and other relevant stakeholders at an international delirium study planning meeting.
There is a paucity of high-level evidence for pharmacological and non-pharmacological interventions in the management of delirium in palliative care. However, multiple delirium guidelines for clinical practice have been developed, with recommendations derived from “expert opinion” for areas where research evidence is lacking. In addition to their potential benefits, limitations of clinical guidelines warrant consideration. Guidelines should be appraised and then adapted for use in a particular setting before implementation. Further research is needed on the evaluation of guidelines, as disseminated and implemented in a clinical setting, focusing on measurable outcomes in addition to their impact on quality of care.
Delirium clinical guidelines are available but the level of evidence is limited. More robust evidence is required for future guideline development.
PMCID: PMC4128754  PMID: 24766743
Delirium; palliative care; practice guidelines
17.  Chlamydomonas reinhardtii thermal tolerance enhancement mediated by a mutualistic interaction with vitamin B12-producing bacteria 
The ISME Journal  2013;7(8):1544-1555.
Temperature is one of the most important environmental factors affecting the growth and survival of microorganisms and in light of current global patterns is of particular interest. Here, we highlight studies revealing how vitamin B12 (cobalamin)-producing bacteria increase the fitness of the unicellular alga Chlamydomonas reinhardtii following an increase in environmental temperature. Heat stress represses C. reinhardtii cobalamin-independent methionine synthase (METE) gene expression coinciding with a reduction in METE-mediated methionine synthase activity, chlorosis and cell death during heat stress. However, in the presence of cobalamin-producing bacteria or exogenous cobalamin amendments C. reinhardtii cobalamin-dependent methionine synthase METH-mediated methionine biosynthesis is functional at temperatures that result in C. reinhardtii death in the absence of cobalamin. Artificial microRNA silencing of C. reinhardtii METH expression leads to nearly complete loss of cobalamin-mediated enhancement of thermal tolerance. This suggests that methionine biosynthesis is an essential cellular mechanism for adaptation by C. reinhardtii to thermal stress. Increased fitness advantage of METH under environmentally stressful conditions could explain the selective pressure for retaining the METH gene in algae and the apparent independent loss of the METE gene in various algal species. Our results show that how an organism acclimates to a change in its abiotic environment depends critically on co-occurring species, the nature of that interaction, and how those species interactions evolve.
PMCID: PMC3721113  PMID: 23486253
bacteria–algae interactions; cobalamin-independent methionine synthase; cobalamin-dependent methionine synthase; gene regulation; stress tolerance; vitamin B12
18.  Risk Factors for Human Immunodeficiency Virus Infection among Brazilian Blood Donors; a Multicenter Case-Control Study Using Audio Computer-Assisted Structured-Interviews 
Vox sanguinis  2013;105(2):91-99.
Although risk factors for HIV infection are known, it is important for blood centers to understand local epidemiology and disease transmission patterns. Current risk factors for HIV infection in blood donors in Brazil were assessed.
A case-control study was conducted at large public blood centers located in four major cities between April 2009 – March 2011. Cases were persons whose donations were confirmed positive by enzyme immunoassays followed by Western Blot confirmation. Audio computer-assisted structured-interviews (ACASI) were completed by all cases and controls. Multivariable logistic regression was used to estimate adjusted odds ratios (AORs) and associated 95% confidence intervals (CIs).
There were 341 cases, including 47 with recently-acquired infection, and 791 controls. Disclosed risk factors for both females and males were sex with an HIV-positive person (adjusted odds ratio (AOR) 11.3, 95% CI [4.1, 31.7]) and being an IVDU or sexual partner of an IVDU (AOR 4.65 [1.8, 11.7]). For female blood donors, additional risk factors were having male sex partners who also are MSM (AOR 13.5 [3.1, 59.8]), and having unprotected sex with multiple sexual partners (AOR 5.19 [2.1, 12.9]). The primary risk factor for male blood donors was MSM activity (AOR 21.6 [8.8, 52.9.]). Behaviors associated with recently-acquired HIV were being a MSM or sex partner of MSM (13.82, [4.7, 40.3]), and IVDU (11.47, [3.0, 43.2]).
Risk factors in blood donors parallel those in the general population in Brazil. Identified risk factors suggest that donor compliance with selection procedures at the participating blood centers is inadequate.
PMCID: PMC3733490  PMID: 23517235
HIV; blood donors; Brazil; risk factors; risk reporting/disclosure; medical informatics
19.  Gold nanorod vaccine for respiratory syncytial virus 
Nanotechnology  2013;24(29):295102.
Respiratory syncytial virus (RSV) is a major cause of pneumonia and wheezing in infants and the elderly, but to date there is no licensed vaccine. We developed a gold nanorod construct that displayed the major protective antigen of the virus, the fusion protein (F). Nanorods conjugated to RSV F were formulated as a candidate vaccine preparation by covalent attachment of viral protein using a layer-by-layer approach. In vitro studies using ELISA, confocal microscopy and circular dichroism revealed that conformation-dependent epitopes were maintained during conjugation, and transmission electron microscopy studies showed that a dispersed population of particles could be achieved. Human dendritic cells treated with the vaccine-induced immune responses in primary human T cells. These results suggest that this vaccine approach may be a potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response.
PMCID: PMC3754908  PMID: 23799651
20.  Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol 
Non-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK’s National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials.
NIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down’s syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7–10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals.
The results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice.
NIHR Portfolio Number
PMCID: PMC4226037  PMID: 25027965
Non-invasive prenatal testing; Cell-free fetal DNA; Aneuploidy; Prenatal diagnosis
21.  What constitutes a high quality discharge summary? A comparison between the views of secondary and primary care doctors 
This study aimed to identify any differences in opinion between UK hospital junior doctors and community General Practitioners (GPs) with respect to the ideal content and characteristics of discharge summaries, and to explore junior doctors’ training for and awareness of post-discharge requirements of GPs.
A piloted anonymous survey was posted to 74 junior doctors at a UK general hospital and 153 local GPs. Doctors were asked to rank discharge summary key content and characteristics in order of importance. GP discharge summary preferences and junior doctor training were also investigated. Non-respondents, identified by non-receipt of a separate participation card, were followed up once.
Thirty-six (49%) junior doctors and 42 (28%) GPs returned completed questionnaires. Accuracy was a priority with 24 (72%) GPs and 28 (88%) junior doctors ranking it most important. Details of medication changes were considered most important by 13 (39%) GPs and 4 (12%) junior doctors. Inadequate training in discharge summary writing was reported by 13 (36%) junior doctors.
Although based on small sample sizes from one location, the level and range of differences in perceived importance of reporting medication changes suggests that many discharge summaries may not currently fulfil GP requirements for managing continuity of care. Results indicate that over a third of junior doctors felt inadequately prepared for writing discharge summaries. There may therefore be both a need and professional support for further training in discharge summary writing, requiring confirmatory research.
PMCID: PMC4207187  PMID: 25341221
Patient discharge; discharge summary; patient transfer; interdisciplinary communication; medical education
22.  Are pharmacy-based minor ailment schemes a substitute for other service providers? 
The British Journal of General Practice  2013;63(612):e472-e481.
Pharmacy-based minor ailment schemes (PMASs) have been introduced throughout the UK to reduce the burden of minor ailments on high-cost settings, including general practice and emergency departments.
This study aimed to explore the effect of PMASs on patient health- and cost-related outcomes; and their impact on general practices.
Design and setting
Community pharmacy-based systematic review.
Standard systematic review methods were used, including searches of electronic databases, and grey literature from 2001 to 2011, imposing no restrictions on language or study design. Reporting was conducted in the form recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and checklist.
Thirty-one evaluations were included from 3308 titles identified. Reconsultation rates in general practice, following an index consultation with a PMAS, ranged from 2.4% to 23.4%. The proportion of patients reporting complete resolution of symptoms after an index PMAS consultation ranged from 68% to 94%. No study included a full economic evaluation. The mean cost per PMAS consultation ranged from £1.44 to £15.90. The total number of consultations and prescribing for minor ailments at general practices often declined following the introduction of PMAS.
Low reconsultation and high symptom-resolution rates suggest that minor ailments are being dealt with appropriately by PMASs. PMAS consultations are less expensive than consultations with GPs. The extent to which these schemes shift demand for management of minor ailments away from high-cost settings has not been fully determined. This evidence suggests that PMASs provide a suitable alternative to general practice consultations. Evidence from economic evaluations is needed to inform the future delivery of PMASs.
PMCID: PMC3693804  PMID: 23834884
community pharmacy services; general practice; pharmacy; primary health care; self care
23.  Diagnostic accuracy and use of non-mydriatic ocular fundus photography by emergency department physicians: Phase II of the FOTO-ED study 
Annals of emergency medicine  2013;62(1):28-33.e1.
During the first phase of the FOTO-ED Study, 13% (44/350;95%CI:9–17%) of patients had an ocular fundus finding, such as papilledema, relevant to their emergency department (ED) management found by non-mydriatic ocular fundus photography reviewed by neuro-opthalmologists. All of these findings were missed by ED physicians (EPs), who only examined 14% of enrolled patients by direct ophthalmoscopy. In the present study, we evaluated the sensitivity of non-mydriatic ocular fundus photography, an alternative to direct ophthalmoscopy, for relevant findings when photographs were made available for use by EPs during routine clinical care.
354 patients presenting to our ED with headache, focal neurologic deficit, visual change, or diastolic blood pressure ≥120 mmHg had non-mydriatic fundus photography obtained (Kowa nonmyd-alpha-D). Photographs were placed on the electronic medical record for EPs review. Identification of relevant findings on photographs by EPs was compared to a reference standard of neuro-ophthalmologist review.
EPs reviewed photographs of 239 patients (68%). 35 patients (10%;95%CI:7–13%) had relevant findings identified by neuro-ophthalmologist review (6 disc edema, 6 grade III/IV hypertensive retinopathy, 7 isolated hemorrhages, 15 optic disc pallor, and 1 retinal vascular occlusion). EPs identified 16/35 relevant findings (sensitivity:46%;95%CI:29–63%), and also identified 289/319 normal findings (specificity:96%; 95%CI:87–94%). EPs reported that photographs were helpful for 125 patients (35%).
EPs used non-mydriatic fundus photographs more frequently than they perform direct ophthalmoscopy, and their detection of relevant abnormalities improved. Ocular fundus photography often assisted ED care even when normal. Non-mydriatic ocular fundus photography offers a promising alternative to direct ophthalmoscopy.
PMCID: PMC3722897  PMID: 23433654
24.  Can structural or functional changes following traumatic brain injury in the rat predict the epileptic outcome? 
Epilepsia  2013;54(7):1240-1250.
Post-traumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, risk of injury, and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE.
Adult male Wistar rats underwent LFPI or sham-injury. Serial MR and PET imaging, and behavioral analyses were performed over six months post-injury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-EEG to assess for PTE. Of the LFPI rats, 52% (n=12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings.
Key findings
MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F-FDG PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at one week, one month, three months, and six months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and non-epileptic groups. However, hippocampal surface shape analysis using high dimensional mapping-large deformation identified significant changes in the ipsilateral hippocampus at one week post-injury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the one week, one month, and three month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination.
These findings suggest PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and non-epileptic animals into the correct group.
PMCID: PMC4032369  PMID: 23718645
Post-traumatic epilepsy; Lateral fluid percussion injury; MRI; PET; Epileptogenesis
25.  Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to lean rats does not impair glucose tolerance or muscle insulin response 
Numerous studies have investigated the effects of isolated CLA supplementation on glucose homeostasis in humans and rodents. However, both the amount and relative abundance of CLA isomers in supplemental form are not representative of what is consumed from natural sources. No study to date has examined the effects of altered CLA isomer content within a natural food source. Our goal was to increase the content of the insulin desensitizing CLAt10,c12 isomer relative to the CLAc9,t11 isomer in cow’s milk by inducing subacute rumenal acidosis (SARA), and subsequently investigate the effects of this milk fat on parameters related to glucose and insulin tolerance in rats.
We fed female rats (~2.5 to 3 months of age) CLA t10,c12 –enriched (SARA) butter or non-SARA butter based diets for 4 weeks in either low (10% of kcal from fat; 0.18% total CLA by weight) or high (60% of kcal from fat; 0.55% total CLA by weight) amounts. In an effort to extend these findings, we then fed rats high (60% kcal) amounts of SARA or non-SARA butter for a longer duration (8 weeks) and assessed changes in whole body glucose, insulin and pyruvate tolerance in comparison to low fat and 60% lard conditions.
There was a main effect for increased fasting blood glucose and insulin in SARA vs. non-SARA butter groups after 4 weeks of feeding (p < 0.05). However, blood glucose and insulin concentration, and maximal insulin-stimulated glucose uptake in skeletal muscle were similar in all groups. Following 8 weeks of feeding, insulin tolerance was impaired by the SARA butter, but not glucose or pyruvate tolerance. The non-SARA butter did not impair tolerance to glucose, insulin or pyruvate.
This study suggests that increasing the consumption of a naturally enriched CLAt10,c12 source, at least in rats, has minimal impact on whole body glucose tolerance or muscle specific insulin response.
PMCID: PMC4083370  PMID: 24956949
Conjugated linoleic acid; Butter; Rats; Glucose tolerance; Insulin tolerance; Insulin-stimulated glucose uptake

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