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1.  Animal models for HIV/AIDS research 
Nature reviews. Microbiology  2012;10(12):852-867.
The AIDS pandemic continues to present us with unique scientific and public health challenges. Although the development of effective antiretroviral therapy has been a major triumph, the emergence of drug resistance requires active management of treatment regimens and the continued development of new antiretroviral drugs. Moreover, despite nearly 30 years of intensive investigation, we still lack the basic scientific knowledge necessary to produce a safe and effective vaccine against HIV-1. Animal models offer obvious advantages in the study of HIV/AIDS, allowing for a more invasive investigation of the disease and for preclinical testing of drugs and vaccines. Advances in humanized mouse models, non-human primate immunogenetics and recombinant challenge viruses have greatly increased the number and sophistication of available mouse and simian models. Understanding the advantages and limitations of each of these models is essential for the design of animal studies to guide the development of vaccines and antiretroviral therapies for the prevention and treatment of HIV-1 infection.
PMCID: PMC4334372  PMID: 23154262
2.  KIR3DL01 Recognition of Bw4 Ligands in the Rhesus Macaque: Maintenance of Bw4 Specificity since the Divergence of Apes and Old World Monkeys 
The identification of MHC class I ligands for rhesus macaque KIRs is fundamental to our basic understanding of KIR and MHC class I co-evolution and to the study of NK cell responses in this non-human primate model for AIDS and other viral diseases. Here we show that Mamu-KIR3DL01, which is expressed by approximately 90% of rhesus macaques, recognizes MHC class I molecules with a Bw4 motif. Primary NK cells expressing Mamu-KIR3DL01 were identified by staining with a mAb herein shown to bind Mamu-KIR3DL01 allotypes with an aspartic acid at position 233. The cytolytic activity of Mamu-KIR3DL01+ NK cells was suppressed by cell lines expressing the Bw4 molecules Mamu-B*007:01, -B*041:01, -B*058:02, and -B*065:01. The Bw4 motif was necessary for Mamu-KIR3DL01 recognition, since substitutions in this region abrogated Mamu-KIR3DL01+ NK cell inhibition. However, the presence of a Bw4 motif was not sufficient for recognition, since another Bw4 molecule, Mamu-B*017:01, failed to suppress the cytolytic activity of these NK cells. Replacement of three residues in Mamu-B*017:01, predicted to be KIR-contacts based on the 3-dimensional structure of the human KIR3DL1-HLA-Bw4 complex, with the corresponding residues at these positions for the other Mamu-Bw4 ligands restored Mamu-KIR3DL01+ NK cell inhibition. These results define the ligand specificity of one of the most polymorphic and commonly expressed KIRs in the rhesus macaque, and reveal similarities in Bw4 recognition by Mamu-KIR3DL01 and human KIR3DL1, despite the absence of an orthologous relationship between these two KIRs or conservation of surface residues predicted to interact with MHC class I ligands.
PMCID: PMC4162532  PMID: 24453246
3.  Cue Reactivity in Smokers: An Event-Related Potential Study 
Drugs-of-abuse may increase the salience of drug cues by sensitizing the dopaminergic (DA) system (Robinson & Berridge, 1993), leading to differential attention to smoking stimuli. Event-related potentials (ERPs) have been used to assess attention to smoking cues but not using an ERP component associated with DA-mediated salience evaluation. In this study the DA-related P2a and the P3, were compared in smokers (N=21) and non-smokers (N=21) during an attention selection cue exposure task including both cigarette and neutral images. We predicted that both the P2a and P3 would be larger to targets than non-targets, but larger to non-target cigarette images than non-target neutral images only in the smokers, reflecting smokers’ evaluation of smoking stimuli as relevant even when they were not targets. Results indicated that smokers showed behavioral cue reactivity, with more false alarms to cigarette images (responding to cigarette images when they were not targets) than non-smokers; however, both smokers and non-smokers had a larger P2a and P3 to cigarette images. Thus, while smokers showed behavioral evidence of differential salience evaluation of the cigarette images, this group difference was not reflected in differential brain activity. These findings may reflect characteristics of the ERPs (both ERP components were smaller in the smokers), the smoking sample (they were not more impulsive, i.e. reward sensitive, than the non-smokers, in contrast to prior studies) and the design (all participants were aware that the aim of the study was related to smoking).
PMCID: PMC4282775  PMID: 23958866
event-related potentials; cue reactivity; nicotine; tobacco; smoking
5.  Genetic variation in protein specific antigen detected prostate cancer and the effect of control selection on genetic association studies 
Only a minority of the genetic component of prostate cancer (PrCa) risk has been explained. Some observed associations of single nucleotide polymorphisms (SNPs) with PrCa might arise from associations of these SNPs with circulating prostate specific antigen (PSA) because PSA values are used to select controls.
We undertook a genome-wide association study (GWAS) of screen detected PrCa (ProtecT 1146 cases and 1804 controls); meta-analysed the results with those from the previously published UK Genetic Prostate Cancer Study (1854 cases and 1437 controls); investigated associations of SNPs with PrCa using either ‘low’ (PSA <0.5ng/ml) or ‘high’ (PSA ≥3ng/ml, biopsy negative) PSA controls; and investigated associations of SNPs with PSA.
The ProtecT GWAS confirmed previously reported associations of PrCa at 3 loci: 10q11.23, 17q24.3 and 19q13.33. The meta-analysis confirmed associations of PrCa with SNPs near 4 previously identified loci (8q24.21,10q11.23, 17q24.3 and 19q13.33). When comparing PrCa cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849 and rs2735839 were associated with an increased risk of PrCa, but the effect-estimates were attenuated to the null when using high PSA controls (p for heterogeneity in effect-estimates<0.04). We found a novel inverse association of rs9311171-T with circulating PSA.
Differences in effect estimates for PrCa observed when comparing low vs. high PSA controls, may be explained by associations of these SNPs with PSA.
These findings highlight the need for inferences from genetic studies of PrCa risk to carefully consider the influence of control selection criteria.
PMCID: PMC4082405  PMID: 24753544
Prostate Specific Antigen; research design; prostate cancer; case-control studies; genome wide association studies
6.  Sonographic evaluation of intravascular volume status: Can internal jugular or femoral vein collapsibility be used in the absence of IVC visualization? 
Annals of Thoracic Medicine  2015;10(1):44-49.
Inferior vena cava collapsibility index (IVC-CI) has been shown to correlate with both clinical and invasive assessment of intravascular volume status, but has important limitations such as the requirement for advanced sonographic skills, the degree of difficulty in obtaining those skills, and often challenging visualization of the IVC in the postoperative patient. The current study aims to explore the potential for using femoral (FV) or internal jugular (IJV) vein collapsibility as alternative sonographic options in the absence of adequate IVC visualization.
A prospective, observational study comparing IVC-CI and Fem- and/or IJV-CI was performed in two intensive care units (ICU) between January 2012 and April 2014. Concurrent M-mode measurements of IVC-CI and FV- and/or IJV-CI were collected during each sonographic session. Measurements of IVC were obtained using standard technique. IJV-CI and FV-CI were measured using high-frequency, linear array ultrasound probe placed in the corresponding anatomic areas. Paired data were analyzed using coefficient of correlation/determination and Bland-Altman determination of measurement bias.
We performed paired ultrasound examination of IVC-IJV (n = 39) and IVC-FV (n = 22), in 40 patients (mean age 54.1; 40% women). Both FV-CI and IJV-CI scans took less time to complete than IVC-CI scans (both, P < 0.02). Correlations between IVC-CI/FV-CI (R2 = 0.41) and IVC-CI/IJV-CI (R2 = 0.38) were weak. There was a mean -3.5% measurement bias between IVC-CI and IJV-CI, with trend toward overestimation for IJV-CI with increasing collapsibility. In contrast, FV-CI underestimated collapsibility by approximately 3.8% across the measured collapsibility range.
Despite small measurement biases, correlations between IVC-CI and FV-/IJV-CI are weak. These results indicate that IJ-CI and FV-CI should not be used as a primary intravascular volume assessment tool for clinical decision support in the ICU. The authors propose that IJV-CI and FV-CI be reserved for clinical scenarios where sonographic acquisition of both IVC-CI or subclavian collapsibility are not feasible, especially when trended over time. Sonographers should be aware that IJV-CI tends to overestimate collapsibility when compared to IVC-CI, and FV-CI tends to underestimates collapsibility relative to IVC-CI.
PMCID: PMC4286845  PMID: 25593607
Femoral vein; hemodynamic resuscitation; intensive care unit; internal jugular vein; inferior vena cava; intravascular volume status assessment; portable ultrasound; point-of-care testing; venous collapsibility index
7.  Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case–control study 
Cancer Causes & Control  2014;26:205-218.
Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer.
In a nested case–control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1–T2/T3–T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism.
We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure.
We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-014-0500-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4298668  PMID: 25488826
Prostate cancer; Vitamin D; Vitamin D pathway genes; 25 hydroxyvitamin-D; 1,25-dihydroxyvitamin-D
8.  Classifying outcomes of care for injured patients 
Canadian Journal of Surgery  2014;57(6):368-370.
Many trauma survivors face challenges of impaired functioning, limited activities and reduced participation. Recovery from injury after acute care, therefore, becomes an important public health issue. This commentary discusses a framework for evaluating outcomes of acute care.
PMCID: PMC4245265  PMID: 25421077
10.  Osteohistological variation in growth marks and osteocyte lacunar density in a theropod dinosaur (Coelurosauria: Ornithomimidae) 
BMC Evolutionary Biology  2014;14(1):231.
Osteohistological examinations of fossil vertebrates have utilized a number of proxies, such as counts and spacing of lines of arrested growth (LAGs) and osteocyte lacunar densities (OLD), in order to make inferences related to skeletochronology and mass-specific growth rates. However, many of these studies rely on samplings of isolated bones from single individuals. These analyses do not take individual variation into account, and as a result may lead to misleading inferences of the physiology of extinct organisms. This study uses a multi-element, multi-individual sampling of ornithomimid dinosaurs to test the amount of individual variation in the aforementioned osteohistological indicators. Based on these results we also assess the conclusions of previous studies that tested paleohistological hypotheses using isolated elements.
LAG number was found to be consistent within the hind limb bones of each individual, with the exception of the fibula, which preserves one additional LAG. Considerable differences in LAG spacing were found between elements of the sampled individuals, with larger variation found in elements of the foot compared with the femur, fibula, and tibia. Osteocyte lacunar density ranged between 29000 and 42000 osteocyte lacunae per mm3, and was found to vary more between hind limb bones of an individual and within bones, than between the average values of individuals.
The variation between hind limb elements in LAG number and LAG spacing suggests that direct comparisons of these elements may be misleading, and that LAG spacing is not a reliable proxy for mass-specific growth rates of an individual. Sampling of multiple bones should be performed as an internal check of model-based LAG retro-calculation and growth equations. The observation that osteocyte lacunar density varies more between individual bone elements than between average individual values suggests that the choice of sampled element can greatly influence the result, and care should be taken to not bias interpretations of the physiology of fossil tetrapods.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-014-0231-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4269922  PMID: 25421260
11.  Error correction and diversity analysis of population mixtures determined by NGS 
PeerJ  2014;2:e645.
The impetus for this work was the need to analyse nucleotide diversity in a viral mix taken from honeybees. The paper has two findings. First, a method for correction of next generation sequencing error in the distribution of nucleotides at a site is developed. Second, a package of methods for assessment of nucleotide diversity is assembled. The error correction method is statistically based and works at the level of the nucleotide distribution rather than the level of individual nucleotides. The method relies on an error model and a sample of known viral genotypes that is used for model calibration. A compendium of existing and new diversity analysis tools is also presented, allowing hypotheses about diversity and mean diversity to be tested and associated confidence intervals to be calculated. The methods are illustrated using honeybee viral samples. Software in both Excel and Matlab and a guide are available at, the Warwick University Systems Biology Centre software download site.
PMCID: PMC4232844  PMID: 25405074
Calibration; Error correction; Honeybee; Metagenome; Nucleotide diversity; Standard sample; Viral mix
12.  Genome Scale Patterns of Recombination between Coinfecting Vaccinia Viruses 
Journal of Virology  2014;88(10):5277-5286.
Recombination plays a critical role in virus evolution. It helps avoid genetic decline and creates novel phenotypes. This promotes survival, and genome sequencing suggests that recombination has facilitated the evolution of human pathogens, including orthopoxviruses such as variola virus. Recombination can also be used to map genes, but although recombinant poxviruses are easily produced in culture, classical attempts to map the vaccinia virus (VACV) genome this way met with little success. We have sequenced recombinants formed when VACV strains TianTan and Dryvax are crossed under different conditions. These were a single round of growth in coinfected cells, five rounds of sequential passage, or recombinants obtained using leporipoxvirus-mediated DNA reactivation. Our studies showed that recombinants contain a patchwork of DNA, with the number of exchanges increasing with passage. Further passage also selected for TianTan DNA and correlated with increased plaque size. The recombinants produced through a single round of coinfection contain a disproportionate number of short conversion tracks (<1 kbp) and exhibited 1 exchange per 12 kbp, close to the ∼1 per 8 kbp in the literature. One by-product of this study was that rare mutations were also detected; VACV replication produces ∼1 × 10−8 mutation per nucleotide copied per cycle of replication and ∼1 large (21 kbp) deletion per 70 rounds of passage. Viruses produced using DNA reactivation appeared no different from recombinants produced using ordinary methods. An attractive feature of this approach is that when it is combined with selection for a particular phenotype, it provides a way of mapping and dissecting more complex virus traits.
IMPORTANCE When two closely related viruses coinfect the same cell, they can swap genetic information through a process called recombination. Recombination produces new viruses bearing different combinations of genes, and it plays an important role in virus evolution. Poxviruses are a family of viruses that includes variola (or smallpox) virus, and although poxviruses are known to recombine, no one has previously mapped the patterns of DNAs exchanged between viruses. We coinfected cells with two different vaccinia poxviruses, isolated the progeny, and sequenced them. We show that poxvirus recombination is a very accurate process that assembles viruses containing DNA copied from both parents. In a single round of infection, DNA is swapped back and forth ∼18 times per genome to make recombinant viruses that are a mosaic of the two parental DNAs. This mixes many different genes in complex combinations and illustrates how recombination can produce viruses with greatly altered disease potential.
PMCID: PMC4019122  PMID: 24574414
13.  Nicotine Deprivation Influences P300 Markers of Cognitive Control 
Neuropsychopharmacology  2013;38(12):2525-2531.
Studies suggest that reduced cognitive control due to nicotine withdrawal may have a critical role in promoting tobacco use. The P3 family of event-related brain potential (ERP) components is thought to serve as markers of cognitive control processes. Unfortunately, existing research that examines the effects of nicotine deprivation on P3 amplitude has been marred by small sample sizes and other design limitations. The present study sought to determine the effects of nicotine deprivation on P3b and P3a amplitudes, which index task relevant target detection and orienting responses to novelty, respectively. A secondary aim was to examine self-reported trait cognitive control as a moderator of nicotine deprivation-induced reductions in P3b and P3a amplitudes. In all, 121 nicotine-dependent smokers attended two experimental sessions following 12-h smoking/nicotine deprivation. In a counterbalanced manner, participants smoked nicotine cigarettes during one session and placebo cigarettes during the other session. Findings indicated that nicotine deprivation reduced P3b amplitude (p<0.00001) during a three-stimulus oddball task independent of trait cognitive control. In contrast, nicotine deprivation reduced P3a only among participants who scored lower on measures of trait cognitive control. Implications for conceptualizing risk for nicotine dependence, and its treatment, are discussed.
PMCID: PMC3799074  PMID: 23807239
Acetylcholine; Addiction & Substance Abuse; Cognition; ERP; Nicotine; P300; Psychopharmacology; Smoking; nicotine; smoking; attention; ERP; P3a; P3b
14.  An In Vitro Comparison of Embolus Differentiation Techniques for Clinically Significant Macroemboli: Dual-Frequency Technique versus Frequency Modulation Method 
Ultrasound in Medicine & Biology  2014;40(11):2642-2654.
The ability to distinguish harmful solid cerebral emboli from gas bubbles intra-operatively has potential to direct interventions to reduce the risk of brain injury. In this in vitro study, two embolus discrimination techniques, dual-frequency (DF) and frequency modulation (FM) methods, are simultaneously compared to assess discrimination of potentially harmful large pieces of carotid plaque debris (0.5–1.55 mm) and thrombus-mimicking material (0.5–2 mm) from gas bubbles (0.01–2.5 mm). Detection of plaque and thrombus-mimic using the DF technique yielded disappointing results, with four out of five particles being misclassified (sensitivity: 18%; specificity: 89%). Although the FM method offered improved sensitivity, a higher number of false positives were observed (sensitivity: 72%; specificity: 50%). Optimum differentiation was achieved using the difference between peak embolus/blood ratio and mean embolus/blood ratio (sensitivity: 77%; specificity: 81%). We conclude that existing DF and FM techniques are unable to confidently distinguish large solid emboli from small gas bubbles (<50 μm).
PMCID: PMC4195753  PMID: 25218455
Embolus detection; Transcranial Doppler ultrasound; Discrimination; Emboli
15.  Genome-wide association study identifies loci affecting blood copper, selenium and zinc 
Human Molecular Genetics  2013;22(19):3998-4006.
Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and >2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10−10, and rs2769264, P = 2.63 × 10−20); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10−28 at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10−12; rs2120019, P = 1.55 × 10−18; and rs4826508, P = 1.40 × 10−12, respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
PMCID: PMC3766178  PMID: 23720494
16.  A systematic review of the need for MRI for the clearance of cervical spine injury in obtunded blunt trauma patients after normal cervical spine CT 
Clearance of cervical spine injury (CSI) in the obtunded or comatose blunt trauma patient remains controversial. In patients with unreliable physical examination and no evidence of CSI on computed tomography (CT), magnetic resonance imaging of the cervical spine (CS-MRI) is the typical follow-up study. There is a growing body of evidence suggesting that CS-MRI is unnecessary with negative findings on a multi-detector CT (MDCT) scan. This review article systematically analyzes current literature to address the controversies surrounding clearance of CSI in obtunded blunt trauma patients. A literature search through MEDLINE database was conducted using all databases on the National Center for Biotechnology Information (NCBI) website ( for keywords: “cervical spine injury,” “obtunded,” and “MRI.” The search was limited to studies published within the last 10 years and with populations of patients older than 18 years old. Eleven studies were included in the analysis yielding data on 1535 patients. CS-MRI detected abnormalities in 256 patients (16.6%). The abnormalities reported on CS-MRI resulted in prolonged rigid c-collar immobilization in 74 patients (4.9%). Eleven patients (0.7%) had unstable injury detected on CS-MRI alone that required surgical intervention. In the obtunded blunt trauma patient with unreliable clinical examination and a normal CT scan, there is still a role for CS-MRI in detecting clinically significant injuries when MRI resources are available. However, when a reliable clinical exam reveals intact gross motor function, CS-MRI may be unnecessary.
PMCID: PMC4231259  PMID: 25400384
Blunt trauma; cervical spine CT and MRI; obtunded
17.  Pre-injury beta blocker use does not affect the hyperdynamic response in older trauma patients 
Trauma dogma dictates that the physiologic response to injury is blunted by beta-blockers and other cardiac medications. We sought to determine how the pre-injury cardiac medication profile influences admission physiology and post-injury outcomes.
Materials and Methods:
Trauma patients older than 45 evaluated at our center were retrospectively studied. Pre-injury medication profiles were evaluated for angiotensin-converting enzyme inhibitors / angiotensin receptor blockers (ACE-I/ARB), beta-blockers, calcium channel blockers, amiodarone, or a combination of the above mentioned agents. Multivariable logistic regression or linear regression analyses were used to identify relationships between pre-injury medications, vital signs on presentation, post-injury complications, length of hospital stay, and mortality.
Records of 645 patients were reviewed (mean age 62.9 years, Injury Severity Score >10, 23%). Our analysis demonstrated no effect on systolic and diastolic blood pressures from beta-blocker, ACE-I/ARB, calcium channel blocker, and amiodarone use. The triple therapy (combined beta-blocker, calcium channel blocker, and ACE-I/ARB) patient group had significantly lower heart rate than the no cardiac medication group. No other groups were statistically different for heart rate, systolic, and diastolic blood pressure.
Pre-injury use of cardiac medication lowered heart rate in the triple-agent group (beta-blocker, calcium channel blocker, and ACEi/ARB) when compared the no cardiac medication group. While most combinations of cardiac medications do not blunt the hyperdynamic response in trauma cases, patients on combined beta-blocker, calcium channel blocker, and ACE-I/ARB therapy had higher mortality and more in-hospital complications despite only mild attenuation of the hyperdynamic response.
PMCID: PMC4231268  PMID: 25400393
Beta-blockers; cardiac medication; geriatric trauma; hyperdynamic response
18.  Monitoring Intervention Coverage in the Context of Universal Health Coverage 
PLoS Medicine  2014;11(9):e1001728.
As part of the Universal Health Coverage Collection, Ties Boerma and colleagues discuss monitoring intervention coverage related to the full spectrum of UHC, including health promotion and disease prevention, treatment, rehabilitation, and palliation.
Please see later in the article for the Editors' Summary
Monitoring universal health coverage (UHC) focuses on information on health intervention coverage and financial protection. This paper addresses monitoring intervention coverage, related to the full spectrum of UHC, including health promotion and disease prevention, treatment, rehabilitation, and palliation. A comprehensive core set of indicators most relevant to the country situation should be monitored on a regular basis as part of health progress and systems performance assessment for all countries. UHC monitoring should be embedded in a broad results framework for the country health system, but focus on indicators related to the coverage of interventions that most directly reflect the results of UHC investments and strategies in each country. A set of tracer coverage indicators can be selected, divided into two groups—promotion/prevention, and treatment/care—as illustrated in this paper. Disaggregation of the indicators by the main equity stratifiers is critical to monitor progress in all population groups. Targets need to be set in accordance with baselines, historical rate of progress, and measurement considerations. Critical measurement gaps also exist, especially for treatment indicators, covering issues such as mental health, injuries, chronic conditions, surgical interventions, rehabilitation, and palliation. Consequently, further research and proxy indicators need to be used in the interim. Ideally, indicators should include a quality of intervention dimension. For some interventions, use of a single indicator is feasible, such as management of hypertension; but in many areas additional indicators are needed to capture quality of service provision. The monitoring of UHC has significant implications for health information systems. Major data gaps will need to be filled. At a minimum, countries will need to administer regular household health surveys with biological and clinical data collection. Countries will also need to improve the production of reliable, comprehensive, and timely health facility data.
Please see later in the article for the Editors' Summary
PMCID: PMC4171108  PMID: 25243586
19.  Monitoring Progress towards Universal Health Coverage at Country and Global Levels 
PLoS Medicine  2014;11(9):e1001731.
As part of the Collection on Monitoring Universal Health Coverage, Ties Boerma and colleagues discuss the key findings from the country case studies and technical reviews included in the Collection and, also, how these papers will help with the development of a global framework for monitoring progress towards Universal Health Coverage.
Please see later in the article for the Editors' Summary
Universal health coverage (UHC) has been defined as the desired outcome of health system performance whereby all people who need health services (promotion, prevention, treatment, rehabilitation, and palliation) receive them, without undue financial hardship. UHC has two interrelated components: the full spectrum of good-quality, essential health services according to need, and protection from financial hardship, including possible impoverishment, due to out-of-pocket payments for health services. Both components should benefit the entire population.
This paper summarizes the findings from 13 country case studies and five technical reviews, which were conducted as part of the development of a global framework for monitoring progress towards UHC.
The case studies show the relevance and feasibility of focusing UHC monitoring on two discrete components of health system performance: levels of coverage with health services and financial protection, with a focus on equity. These components link directly to the definition of UHC and measure the direct results of strategies and policies for UHC. The studies also show how UHC monitoring can be fully embedded in often existing, regular overall monitoring of health sector progress and performance. Several methodological and practical issues related to the monitoring of coverage of essential health services, financial protection, and equity, are highlighted. Addressing the gaps in the availability and quality of data required for monitoring progress towards UHC is critical in most countries.
PMCID: PMC4171369  PMID: 25243899
20.  Financial Risk Protection and Universal Health Coverage: Evidence and Measurement Challenges 
PLoS Medicine  2014;11(9):e1001701.
As part of a PLOS Collection on universal health coverage, Priyanka Saksena and colleagues examine existing measures of financial risk protection and suggest future developments that could be valuable in monitoring progress towards universal health coverage.
Financial risk protection is a key component of universal health coverage (UHC), which is defined as access to all needed quality health services without financial hardship. As part of the PLOS Medicine Collection on measurement of UHC, the aim of this paper is to examine and to compare and contrast existing measures of financial risk protection. The paper presents the rationale behind the methodologies for measuring financial risk protection and how this relates to UHC as well as some empirical examples of the types of measures. Additionally, the specific challenges related to monitoring inequalities in financial risk protection are discussed. The paper then goes on to examine and document the practical challenges associated with measurement of financial risk protection. This paper summarizes current thinking on the area of financial risk protection, provides novel insights, and suggests future developments that could be valuable in the context of monitoring progress towards UHC.
PMCID: PMC4171370  PMID: 25244520
21.  Vaccine-Induced Env V1–V2 IgG3 Correlates with Lower HIV-1 Infection Risk and Declines Soon After Vaccination 
Science translational medicine  2014;6(228):228ra39.
HIV-1–specific immunoglobulin G (IgG) subclass antibodies bind to distinct cellular Fc receptors. Antibodies of the same epitope specificity but of a different subclass therefore can have different antibody effector functions. The study of IgG subclass profiles between different vaccine regimens used in clinical trials with divergent efficacy outcomes can provide information on the quality of the vaccine-induced B cell response. We show that HIV-1–specific IgG3 distinguished two HIV-1 vaccine efficacy studies (RV144 and VAX003 clinical trials) and correlated with decreased risk of HIV-1 infection in a blinded follow-up case-control study with the RV144 vaccine. HIV-1–specific IgG3 responses were not long-lived, which was consistent with the waning efficacy of the RV144 vaccine. These data suggest that specific vaccine-induced HIV-1 IgG3 should be tested in future studies of immune correlates in HIV-1 vaccine efficacy trials.
PMCID: PMC4116665  PMID: 24648342
22.  Role of Nicotine Dependence on the Relationship between Variants in the Nicotinic Receptor Genes and Risk of Lung Adenocarcinoma 
PLoS ONE  2014;9(9):e107268.
Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four ‘control’ genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10−10 and 1.1×10−10, respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.
PMCID: PMC4169410  PMID: 25233467
23.  Mercury Exposure in Ireland: Results of the DEMOCOPHES Human Biomonitoring Study 
Background: Monitoring of human exposure to mercury is important due to its adverse health effects. This study aimed to determine the extent of mercury exposure among mothers and their children in Ireland, and to identify factors associated with elevated levels. It formed part of the Demonstration of a study to Coordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES) pilot biomonitoring study. Methods: Hair mercury concentrations were determined from a convenience sample of 120 mother/child pairs. Mothers also completed a questionnaire. Rigorous quality assurance within DEMOCOPHES guaranteed the accuracy and international comparability of results. Results: Mercury was detected in 79.2% of the samples from mothers, and 62.5% of children’s samples. Arithmetic mean levels in mothers (0.262 µg/g hair) and children (0.149 µg /g hair) did not exceed the US EPA guidance value. Levels were significantly higher for those with higher education, and those who consumed more fish. Conclusions: The study demonstrates the benefit of human biomonitoring for assessing and comparing internal exposure levels, both on a population and an individual basis. It enables the potential harmful impact of mercury to be minimised in those highly exposed, and can therefore significantly contribute to population health.
PMCID: PMC4199048  PMID: 25233018
mercury; human biomonitoring; hair; exposure
24.  A low cost, high fidelity nerve block model 
We have constructed a simple, inexpensive simulation model for ultrasound guided nerve blocks. To date there are no low cost, high fidelity models for nerve block simulations. The models that do exist are expensive and vaguely resemble actual anatomy. As ultrasound guided nerve blocks become more common in medical education it is essential to develop better training models to help increase the comfort level of the individual provider and increase the chances for success during live-patient procedures [Anaesth Intensive Care 37: 824-829, 2009].
The nerve block model was produced with a single pork loin with pressure-injected ultrasound gel through both CAT 5 cable and IV tubing inserted length-wise into the pork loin.
Our nerve block model had a realistic, life-like feel simulating human tissue.
This ultrasound nerve block model was inexpensive with life-like feel allowing resident trainees to develop more confidence and tactile skill to increase the chance for success.
PMCID: PMC4233329  PMID: 25411589
Regional anesthesia; Ultrasound; Phantom model; Nerve block
25.  MosaicSolver: a tool for determining recombinants of viral genomes from pileup data 
Nucleic Acids Research  2014;42(16):e123.
Viral recombination is a key evolutionary mechanism, aiding escape from host immunity, contributing to changes in tropism and possibly assisting transmission across species barriers. The ability to determine whether recombination has occurred and to locate associated specific recombination junctions is thus of major importance in understanding emerging diseases and pathogenesis. This paper describes a method for determining recombinant mosaics (and their proportions) originating from two parent genomes, using high-throughput sequence data. The method involves setting the problem geometrically and the use of appropriately constrained quadratic programming. Recombinants of the honeybee deformed wing virus and the Varroa destructor virus-1 are inferred to illustrate the method from both siRNAs and reads sampling the viral genome population (cDNA library); our results are confirmed experimentally. Matlab software (MosaicSolver) is available.
PMCID: PMC4176379  PMID: 25120266

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