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1.  The Rise and Fall of the Lyme Disease Vaccines: A Cautionary Tale for Risk Interventions in American Medicine and Public Health 
The Milbank Quarterly  2012;90(2):250-277.
Context
Two vaccines to prevent Lyme disease (LD) were developed and tested in the 1990s. Despite evidence of their safety and efficacy in clinical trials and initial postmarketing surveillance, one vaccine was withdrawn before the regulatory review and the other after only three years on the market. An investigation of their history can illuminate (1) the challenges faced by many new risk-reducing products and practices and (2) the important role played by their social and psychological, as distinct from their biomedical or scientific, efficacy in how they are used, and their ultimate market success or failure.
Methods
This article reviewed medical and popular literature on LD vaccines, analyzed the regulatory hearings, and conducted interviews with key participants.
Findings
Even if proved safe and effective, LD vaccines faced regulatory and market challenges because the disease was geographically limited, treatable, and preventable by other means. Pharmaceutical companies nevertheless hoped to appeal to consumers’ desire for protection and control and to their widespread fear of the disease. The LD advocacy community initially supported the vaccines but soon became critical opponents. The vaccines’ success was seen as threatening their central position that LD was chronic, protean, and difficult to treat. The activists’ opposition flipped the vaccines’ social and psychological efficacy. Instead of the vaccines restoring control and reducing fear, demand was undermined by beliefs that the vaccines caused an LD-like syndrome.
Conclusions
The social and psychological efficacy of many risk-reducing practices and products, such as new “personalized vaccines,” is to provide insurance and reduce fear. Yet the actions of self-interested actors can easily undermine this appeal. In addition to evaluating the scientific efficacy and safety of these practices and products, policymakers and others need to understand, anticipate, and perhaps shape the potential social and psychological work they might do.
doi:10.1111/j.1468-0009.2012.00663.x
PMCID: PMC3460208  PMID: 22709388
Lyme disease; Lyme disease vaccines; history of medicine; history of public health; vaccines; health policy
2.  Contrasting Microbial Community Assembly Hypotheses: A Reconciling Tale from the Río Tinto 
PLoS ONE  2008;3(12):e3853.
Background
The Río Tinto (RT) is distinguished from other acid mine drainage systems by its natural and ancient origins. Microbial life from all three domains flourishes in this ecosystem, but bacteria dominate metabolic processes that perpetuate environmental extremes. While the patchy geochemistry of the RT likely influences the dynamics of bacterial populations, demonstrating which environmental variables shape microbial diversity and unveiling the mechanisms underlying observed patterns, remain major challenges in microbial ecology whose answers rely upon detailed assessments of community structures coupled with fine-scale measurements of physico-chemical parameters.
Methodology/Principal Findings
By using high-throughput environmental tag sequencing we achieved saturation of richness estimators for the first time in the RT. We found that environmental factors dictate the distribution of the most abundant taxa in this system, but stochastic niche differentiation processes, such as mutation and dispersal, also contribute to observed diversity patterns.
Conclusions/Significance
We predict that studies providing clues to the evolutionary and ecological processes underlying microbial distributions will reconcile the ongoing debate between the Baas Becking vs. Hubbell community assembly hypotheses.
doi:10.1371/journal.pone.0003853
PMCID: PMC2587236  PMID: 19052647
3.  Cytogenetic and molecular study of the PRDX4 gene in a translocation (X;18)(p22;q23) – a cautionary tale 
Cancer genetics and cytogenetics  2007;176(2):131-136.
The PRDX4 gene located at Xp22 codes for a member of the peroxiredoxin gene family. Genes within this family exhibit thioredoxin-dependent peroxidase activity and have been implicated in cellular functioning, including proliferation and differentiation. Recently, PRDX4 has been identified as a partner gene in an X;21 translocation in a patient with acute myeloid leukemia (AML). To determine whether PRDX4 was involved in other translocations, leukemia cells from fifteen patients with Xp22 abnormalities were screened for the gene’s involvement using fluorescence in situ hybridization (FISH). One sample from a 41 year old female with acute lymphoblastic leukemia (ALL) showed three signals when hybridized with the PRDX4 probe. Cytogenetic analysis of the sample had identified a t(X;18)(p22,q23). Assuming that the three signals indicated a break within the PRDX4 gene, we performed FISH experiments and successfully narrowed the breakpoint on chromosome 18 to a 50 kB region. Subsequent analysis using spectral karyotyping showed that the leukemic cells had undergone multiple rearrangements and that a third X chromosome, albeit rearranged, was present. Additional FISH experiments revealed that the third PRDX4 signal was the result of a third copy of the gene. Analysis of the other rearrangements has helped to characterize the multiple abnormalities within the leukemic cells. Our findings are significant because they underline the importance of using multiple techniques when analyzing complex chromosomal rearrangements in malignant cells.
doi:10.1016/j.cancergencyto.2007.03.010
PMCID: PMC2083648  PMID: 17656256
4.  The Perils of Partialling: Cautionary Tales From Aggression and Psychopathy 
Assessment  2006;13(3):328-341.
Although a powerful technique, the partialling of independent variables from one another in the context of multiple regression analysis poses certain perils. The present article argues that the most important and underappreciated peril is the difficulty in knowing what construct an independent variable represents once the variance shared with other independent variables is removed. The present article presents illustrative analyses in a large sample of inmates (n = 696) using three measures from the psychopathy and aggression fields. Results indicate that in terms of relations among items on a single scale and relations between scales, the raw and residualized scores bore little resemblance to one another. It is argued that researchers must decide to which construct—the one represented by the original scale or the one represented by the residualized scale—conclusions are meant to apply. Difficulties in applying the conclusions to the residualized scale are highlighted and best practices suggested.
doi:10.1177/1073191106290562
PMCID: PMC3152746  PMID: 16880283
psychopathy; aggression; partialling; suppression
5.  Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? 
Brain  2012;135(11):3206-3226.
Tremor in Parkinson's disease has several mysterious features. Clinically, tremor is seen in only three out of four patients with Parkinson's disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion in Parkinson's disease, and the cerebello-thalamo-cortical circuit, which is also involved in many other tremors. The purpose of this review is to integrate these clinical and pathophysiological features of tremor in Parkinson's disease. We first describe clinical and pathological differences between tremor-dominant and non-tremor Parkinson's disease subtypes, and then summarize recent studies on the pathophysiology of tremor. We also discuss a newly proposed ‘dimmer-switch model’ that explains tremor as resulting from the combined actions of two circuits: the basal ganglia that trigger tremor episodes and the cerebello-thalamo-cortical circuit that produces the tremor. Finally, we address several important open questions: why resting tremor stops during voluntary movements, why it has a variable response to dopaminergic treatment, why it indicates a benign Parkinson's disease subtype and why its expression decreases with disease progression.
doi:10.1093/brain/aws023
PMCID: PMC3501966  PMID: 22382359
Parkinson's disease; tremor; basal ganglia; cerebellum, thalamus
6.  Pattern of Social Interactions after Group Integration: A Possibility to Keep Stallions in Group 
PLoS ONE  2013;8(1):e54688.
Horses are often kept in individual stables, rather than in outdoor groups, despite such housing system fulfilling many of their welfare needs, such as the access to social partners. Keeping domestic stallions in outdoor groups would mimic bachelor bands that are found in the wild. Unfortunately, the high level of aggression that unfamiliar stallions display when they first encounter each other discourages owners from keeping them in groups. However, this level of aggression is likely to be particularly important only during group integration, when the dominance hierarchy is being established, whereas relatively low aggression rates have been observed among stable feral bachelor bands. We investigated the possibility of housing breeding stallions owned by the Swiss National Stud in groups on a large pasture (5 stallions in 2009 and 8 stallions in 2010). We studied the pattern of agonistic, ritual and affiliative interactions after group integration (17–23 days), and the factors influencing these interactions (time after group integration, dominance rank, age or experience of group housing). We found that stallions displayed generally more ritual than agonistic and than affiliative interactions. The frequency of agonistic and ritual interactions decreased quickly within the first three to four days. The frequency of affiliative interactions increased slowly with time before decreasing after 9–14 days. A stable hierarchy could be measured after 2–3 months. The highest-ranking males had less ritual interactions than the lowest-ranking. Males had also less agonistic, ritual and affiliative interactions if they had already been housed in a group the previous year. Therefore, we found that breeding stallions could be housed together on a large pasture, because the frequency of agonistic interactions decreased quickly and remained at a minimal level from the fourth day following group integration. This housing system could potentially increase horse welfare and reduce labour associated with horse management.
doi:10.1371/journal.pone.0054688
PMCID: PMC3559779  PMID: 23382940
7.  Reduced inclination of cervical spine in a novel notebook screen system - implications for rehabilitation 
Background
Professional working at computer notebooks is associated with high requirements on the body posture in the seated position. By the high continuous static muscle stress resulting from this position at notebooks, professionals frequently working at notebooks for long hours are exposed to an increased risk of musculoskeletal complaints. Especially in subjects with back pain, new notebooks should be evaluated with a focus on rehabilitative issues.
Methods
In a field study a new notebook design with adjustable screen was analyzed and compared to standard notebook position.
Results
There are highly significant differences in the visual axis of individuals who are seated in the novel notebook position in comparison to the standard position. Also, differences are present between further alternative notebook positions. Testing of gender and glasses did not reveal influences.
Conclusion
This study demonstrates that notebooks with adjustable screen may be used to improve the posture. Future studies may focus on patients with musculoskeletal diseases.
doi:10.1186/1745-6673-6-30
PMCID: PMC3253038  PMID: 22118159
8.  The Surgical Treatment of Carbuncles: A Tale of Two Techniques 
The treatment of carbuncles is early administration of antibiotics and surgery. The commonest surgical approaches are saucerization, and incision and drainage (I&D). Although these two techniques are vastly different, there is a lack of evidence to determine which one produces a better outcome. Three cases of carbuncles are presented to illustrate the contrasting surgical techniques and their results. Three consecutive patients who presented to this hospital with carbuncles were treated with either saucerization or I&D. They were followed up for 8 weeks to assess their outcome. One patient had saucerization while two other patients underwent I&D of their carbuncles. Saucerization produced the shortest length of hospital stay. I&D resulted in earlier wound healing. A randomized controlled is needed to determine the best surgical approach for the treatment of carbuncles.
doi:10.5812/ircmj.2992
PMCID: PMC3785916  PMID: 24083015
Surgery; Carbuncle; Debridement
9.  A tale of two symmetrons: rules for construction of icosahedral capsids from trisymmetrons and pentasymmetrons 
Journal of structural biology  2009;170(1):10.1016/j.jsb.2009.12.003.
The capsids of large, icosahedral dsDNA viruses are built from well-ordered aggregates of capsomers, known as trisymmetrons and pentasymmetrons, which are centered on the icosahedral 3-fold and 5-fold axes respectively. We derive the complete set of rules for constructing an icosahedral structure from these symmetrons when the T lattice symmetry is odd and show that there are three classes of solutions, each of which follows from a different relationship between the size of the pentasymmetron and the values of the h and k icosahedral lattice parameters. Together, these three classes account for all possible ways of building an icosahedral structure solely from trisymmetrons and pentasymmetrons. Also, every icosahedral lattice with odd T number has solutions from exactly two of these three classes, with the set of allowed classes dependent on which of the two lattice parameters is odd. For symmetric lattices (if h=k or h=0), the two solutions yield the same symmetron sizes, but when the lattice parameters are equal (h=k) the solutions can be distinguished by the relative orientations of the symmetrons. We discuss these results in the context of known virus structures and explore the implications for viruses whose structures have not yet been solved.
doi:10.1016/j.jsb.2009.12.003
PMCID: PMC3834589  PMID: 19963064
icosahedral symmetry; trisymmetron; pentasymmetron; capsomer; large DNA virus; virus capsid structure; triangulation number
10.  A tale of three cities: persisting high HIV prevalence, risk behaviour and undiagnosed infection in community samples of men who have sex with men 
Sexually Transmitted Infections  2007;83(5):392-396.
Objectives
To examine the geographical variations in HIV prevalence (diagnosed and undiagnosed), use of sexual health services, sexually transmitted infections and sexual behaviour in a community sample of men who have sex with men in three cities in England, specifically London, Brighton and Manchester.
Methods
Cross‐sectional surveys of men visiting gay community venues in three large cities in England. Men self‐completed a questionnaire and provided an anonymous oral fluid sample for HIV antibody testing.
Results
HIV prevalence ranged from 8.6% to 13.7% in the three cities. Over one‐third of HIV infection remained undiagnosed in all sites despite 69% of HIV‐positive men reporting attending a genitourinary medicine clinic in the last year. Similar and high levels of risk behaviour were reported in all three cities. 18% of HIV‐negative men and 37% of HIV‐positive men reported unprotected anal intercourse with more than one partner in the last year. 20% of negative men and 41% of positive men reported an STI in the last year.
Conclusions
Across all cities, despite widespread availability of anti‐retroviral treatment and national policy to promote HIV testing, many HIV infections remain undiagnosed. Data from this community sample demonstrate high levels of risk behaviour and STI incidence, especially among those who are HIV positive. Renewed efforts are needed to increase diagnosis and to reduce risk behaviour to stem the continuing transmission of HIV.
doi:10.1136/sti.2006.021782
PMCID: PMC2659037  PMID: 17472978
11.  Mustard's operation for patients with ventriculoarterial concordance. Report of two cases and a cautionary tale. 
British Heart Journal  1985;53(4):443-450.
Three patients with ventriculoarterial concordance and an abnormal atrioventricular connexion were investigated. One patient had total anomalous pulmonary venous connexion to a left vertical vein. In 1972 this was repaired and a ventricular septal defect was closed, but the presence of atrioventricular discordance was missed and the patient died. In the other two patients, Mustard's operation resulted in survival. One patient had situs solitus and atrioventricular discordance with an associated ventricular septal defect, which was closed. The other had left isomerism (quasi solitus) with an ambiguous atrioventricular connexion (quasi discordant). A previously noted ventricular septal defect had spontaneously closed.
Images
PMCID: PMC481786  PMID: 3986058
12.  The many faces of translational research: a tale of two studies 
Translational research can take many forms: bench to bedside, across cultural groups, across geographical boundaries, among others. This case study will share how we addressed all three “translational” issues using two evidence-based studies (USA, Zambia) to illustrate these “roads less traveled.” Our implementation and dissemination efforts were anchored by the “train the trainer” strategy, and the Glasgow RE-AIM model provided programmatic guideposts and direction. Keeping all stakeholders (scientific, community, political) involved in the implementation and dissemination process was an essential, perhaps determining factor in the success of the translation process.
doi:10.1007/s13142-011-0044-0
PMCID: PMC3135386  PMID: 21765882
HIV prevention; Sexual risk reduction; Training of trainers; RE-AIM; Translational research; Women and couples living with HIV
13.  The many faces of translational research: a tale of two studies 
ABSTRACT
Translational research can take many forms: bench to bedside, across cultural groups, across geographical boundaries, among others. This case study will share how we addressed all three “translational” issues using two evidence-based studies (USA, Zambia) to illustrate these “roads less traveled.” Our implementation and dissemination efforts were anchored by the “train the trainer” strategy, and the Glasgow RE-AIM model provided programmatic guideposts and direction. Keeping all stakeholders (scientific, community, political) involved in the implementation and dissemination process was an essential, perhaps determining factor in the success of the translation process.
doi:10.1007/s13142-011-0044-0
PMCID: PMC3135386  PMID: 21765882
HIV prevention; Sexual risk reduction; Training of trainers; RE-AIM; Translational research; Women and couples living with HIV
14.  A connected tale of claudins from the renal duct to the sensory system 
Tissue barriers  2013;1(3):e24968.
Summary
Claudins are tight junction membrane proteins that regulate paracellular permeability to ions and solutes in many physiological systems. The electric property of claudin is the most interesting and pertains to two important organ functions: the renal and sensorineural functions. The kidney comprises of three major segments of epithelial tubules with different paracellular permeabilities: the proximal tubule (PT), the thick acending limb of Henle’s loop (TALH) and the collecting duct (CD). Claudins act as ion channels allowing selective permeation of Na+ in the PT, Ca++ and Mg++ in the TALH and Cl− in the CD. The inner ear, on the other hand, expresses claudins as a barrier to block K+ permeation between endolymph and perilymph. The permeability properties of claudins in different organs can be attributed to claudin interaction within the cell membrane and between neighboring cells. The first extracellular loop of claudins contains determinants of paracellular ionic permeability. A novel instrumental technique, based on the Scanning Ion Conductance Microscopy (SICM), has revealed paracellular transport processes with nanoscale spatial resolution. While analogous to transmembrane ion channels in many ways, the biophysical and biochemical properties of claudin based paracellular channels remain to be fully characterized.
doi:10.4161/tisb.24968
PMCID: PMC3867513  PMID: 24533254
tight junction; ion channel; kidney; hypercalciuria; transgenic animal
15.  A connected tale of claudins from the renal duct to the sensory system 
Tissue Barriers  2013;1(3):e24968.
Claudins are tight junction membrane proteins that regulate paracellular permeability to ions and solutes in many physiological systems. The electric property of claudin is the most interesting and pertains to two important organ functions: the renal and sensorineural functions. The kidney comprises of three major segments of epithelial tubules with different paracellular permeabilities: the proximal tubule (PT), the thick acending limb of Henle’s loop (TALH) and the collecting duct (CD). Claudins act as ion channels allowing selective permeation of Na+ in the PT, Ca2+ and Mg2+ in the TALH and Cl− in the CD. The inner ear, on the other hand, expresses claudins as a barrier to block K+ permeation between endolymph and perilymph. The permeability properties of claudins in different organs can be attributed to claudin interaction within the cell membrane and between neighboring cells. The first extracellular loop of claudins contains determinants of paracellular ionic permeability. While analogous to transmembrane ion channels in many ways, the biophysical and biochemical properties of claudin based paracellular channels remain to be fully characterized.
doi:10.4161/tisb.24968
PMCID: PMC3867513  PMID: 24533254
tight junction; ion channel; kidney; hypercalciuria; transgenic animal
16.  Two- and three-input TALE-based AND logic computation in embryonic stem cells 
Nucleic Acids Research  2013;41(21):9967-9975.
Biological computing circuits can enhance our ability to control cellular functions and have potential applications in tissue engineering and medical treatments. Transcriptional activator-like effectors (TALEs) represent attractive components of synthetic gene regulatory circuits, as they can be designed de novo to target a given DNA sequence. We here demonstrate that TALEs can perform Boolean logic computation in mammalian cells. Using a split-intein protein-splicing strategy, we show that a functional TALE can be reconstituted from two inactive parts, thus generating two-input AND logic computation. We further demonstrate three-piece intein splicing in mammalian cells and use it to perform three-input AND computation. Using methods for random as well as targeted insertion of these relatively large genetic circuits, we show that TALE-based logic circuits are functional when integrated into the genome of mouse embryonic stem cells. Comparing construct variants in the same genomic context, we modulated the strength of the TALE-responsive promoter to improve the output of these circuits. Our work establishes split TALEs as a tool for building logic computation with the potential of controlling expression of endogenous genes or transgenes in response to a combination of cellular signals.
doi:10.1093/nar/gkt758
PMCID: PMC3834826  PMID: 23982518
17.  Tales from the Jazz ASH: highlights from the 2013 American Society of Haematology meeting 
ecancermedicalscience  2014;8:390.
The 55th annual ASH meeting was held in pleasant New Orleans and was the largest in its history, with 22,495 participants coming from 113 nations. A ‘bench-to-bedside and back’ attitude characterises haematology probably more than any other discipline in medicine and, as usual, this was reflected in the extremely wide breadth of the topics covered, including the last results from clinical trials and cutting-edge advancements in basic science. This year, the balance was arguably skewed: few truly clinical practice-changing results were presented. On the other hand, a great number of basic and translational studies significantly increased our understanding of the biology of numerous malignancies and heralded the coming of age of disruptive technologies. Namely, above all, next generation sequencing and T cell engineering-based cell therapy.
doi:10.3332/ecancer.2014.390
PMCID: PMC3905784  PMID: 24678345
myeloid malignancies; lymphoid malignancies; targeted therapy; drug discovery; tyrosine kinase inhibitors; chimeric antigen receptors
18.  Characterization of PREP2, a paralog of PREP1, which defines a novel sub-family of the MEINOX TALE homeodomain transcription factors 
Nucleic Acids Research  2002;30(9):2043-2051.
TALE (three amino acid loop extension) homeodomain proteins include the PBC and the MEINOX sub-families. MEINOX proteins form heterodimer complexes with PBC proteins. Heterodimerization is crucial to DNA binding and for nuclear localization. PBC–MEINOX heterodimers bind DNA also in combination with HOX proteins, thereby modulating their DNA-binding specificity. TALE proteins therefore play crucial roles in multiple developmental and differentiation pathways in vivo. We report the identification and characterization of a novel human gene homologous to PREP1, called PREP2. Sequence comparisons indicate that PREP1 and PREP2 define a novel sub-family of MEINOX proteins, distinct from the MEIS sub-family. PREP2 is expressed in a variety of human adult tissues and displays a more restricted expression pattern than PREP1. PREP2 is capable of heterodimerizing with PBC proteins. Heterodimerization with PBX1 appears to be essential for nuclear localization of both PREP2 and PBX1. A comparison between the functional properties of PREP1 and PREP2 reveals that PREP2–PBX display a faster DNA-dissociation rate than PREP1–PBX heterodimers, suggesting different roles in controlling gene expression. Like PREP1, PREP2–PBX heterodimers are capable of forming ternary complexes with HOXB1. The analysis of some PREP2 in vitro properties suggests a functional diversification among PREP and between PREP and MEIS MEINOX proteins.
PMCID: PMC113854  PMID: 11972344
19.  Geminiviruses: a tale of a plasmid becoming a virus 
Background
Geminiviruses (family Geminiviridae) are small single-stranded (ss) DNA viruses infecting plants. Their virion morphology is unique in the known viral world – two incomplete T = 1 icosahedra are joined together to form twinned particles. Geminiviruses utilize a rolling-circle mode to replicate their genomes. A limited sequence similarity between the three conserved motifs of the rolling-circle replication initiation proteins (RCR Reps) of geminiviruses and plasmids of Gram-positive bacteria allowed Koonin and Ilyina to propose that geminiviruses descend from bacterial replicons.
Results
Phylogenetic and clustering analyses of various RCR Reps suggest that Rep proteins of geminiviruses share a most recent common ancestor with Reps encoded on plasmids of phytoplasmas, parasitic wall-less bacteria replicating both in plant and insect cells and therefore occupying a common ecological niche with geminiviruses. Capsid protein of Satellite tobacco necrosis virus was found to be the best template for homology-based structural modeling of the geminiviral capsid protein. Good stereochemical quality of the generated models indicates that the geminiviral capsid protein shares the same structural fold, the viral jelly-roll, with the vast majority of icosahedral plant-infecting ssRNA viruses.
Conclusion
We propose a plasmid-to-virus transition scenario, where a phytoplasmal plasmid acquired a capsid-coding gene from a plant RNA virus to give rise to the ancestor of geminiviruses.
doi:10.1186/1471-2148-9-112
PMCID: PMC2702318  PMID: 19460138
20.  A tale of three aspirations: foreign bodies in the airway 
Journal of Clinical Pathology  2003;56(10):791-794.
Tracheobronchial foreign body aspiration is a serious medical problem, with clinical manifestations ranging from acute asphyxiation to insidious lung damage, as demonstrated by the three presented cases. Patient 1 aspirated during dinner, emergency bronchoscopy retrieved pieces of food, and she fully recovered the following day. Patient 2 presented with recurrent pneumonia and a right lower lobe lung abscess. After right lower lobectomy, pathology revealed a foreign object in the right main stem bronchus, a peanut aspirated one year earlier. Patient 3 became unresponsive several days after spinal surgery. The differential diagnosis included myocardial infarction, stroke, and foreign body aspiration. The patient died and necropsy revealed a foreign body in the right main stem bronchus (cooked meat). Thus, foreign body aspiration is not always suspected clinically, and the pathologist may play an important role in making the diagnosis. Histological identification of the aspirated material may be necessary for definitive diagnosis. Therefore, sections of commonly aspirated foods are presented, together with a 10 year history of aspirated objects received by this institution’s surgical pathology department.
PMCID: PMC1770072  PMID: 14514789
aspiration pneumonia; bronchial obstruction; foreign body aspiration
21.  Population-Based Estimates of Physical Activity for Adults with Type 2 Diabetes: A Cautionary Tale of Potential Confounding by Weight Status  
Journal of Obesity  2010;2011:561432.
At a population level, the method used to determine those meeting physical activity guidelines has important implications, as estimating “sufficient” physical activity might be confounded by weight status. The objective of this study was to test the difference between three methods in estimating the prevalence of “sufficient activity” among Canadian adults with type 2 diabetes in a large population sample (N = 1614) while considering the role of weight status as a potential confounder. Our results revealed that estimates of physical activity levels vary by BMI categories, depending on the methods examined. Although physical activity levels were lower in the obese, their energy expenditure estimates were not different from those who were overweight or of a healthy weight. The implications of these findings are that biased estimates of physical activity at a population level may result in inappropriate classification of adults with type 2 diabetes as “sufficiently active” and that the inclusion of body weight in estimating physical activity prevalence should be approached with caution.
doi:10.1155/2011/561432
PMCID: PMC2943130  PMID: 20871829
22.  A tale of two cultures 
Canadian Family Physician  2011;57(5):576-584.
Abstract
Objective
To understand what contributes to good collaborative physician working relationships through identifying the factors that affect working relationships between generalist physicians and specialists.
Design
Qualitative study using in-depth interviews.
Setting
University and community hospital inpatient family practice settings in Edmonton, Alta.
Participants
Eleven physicians from various specialties who graduated between 1977 and 2001.
Methods
A grounded-theory approach, including constant comparison and creation of memorandums, helped to conceptualize the main concern and generated a framework for how the main concern was being resolved. A semistructured interview guide was developed and individual, in-depth interviews were audiotaped. Purposeful and theoretical sampling techniques were used. Three researchers participated in the analysis.
Main findings
The findings suggested that when generalist physicians perceived that work had been imposed on them by specialists without negotiation, they felt overwhelmed by the workload. Differing priorities determined whether physicians were left holding the bag or sharing the load. In a system that valued technology and specialized knowledge and skills, the specialists were better able to control resources, set boundaries, and influence learners. This precipitated a culture of protecting valuable specialty resources, increasing physician isolation, and generalists feeling that they were left holding the bag. In order to reverse this cycle, it was important for physicians to develop good working relationships based on accessibility to needed expertise and tests, with negotiated agreements on how to share resources; mutual empowerment, including negotiation of roles and responsibilities to develop flexible relationships with a clear understanding of roles; and concern for fairness by sharing the load.
Conclusion
Medical systems that value technology and focused interests might lead to someone being left holding the bag, contributing to generalists feeling overwhelmed and isolated within the system. A comprehensive system that values relationships might help to resolve issues created through perceived inequities in workload, disempowerment, and lack of understanding of roles.
PMCID: PMC3093596  PMID: 21642740
23.  A Tale of Two ObesCities: The Role of Municipal Governance in Reducing Childhood Obesity in New York City and London 
As rates of childhood obesity and overweight rise around the world, researchers and policy makers seek new ways to reverse these trends. Given the concentration of the world’s population, income inequalities, unhealthy diets, and patterns of physical activity in cities, urban areas bear a disproportionate burden of obesity. To address these issues, in 2008, researchers from the City University of New York and London Metropolitan University created the Municipal Responses to Childhood Obesity Collaborative. The Collaborative examined three questions: What role has city government played in responding to childhood obesity in each jurisdiction? How have municipal governance structures in each city influenced its capacity to respond effectively? How can policy and programmatic interventions to reduce childhood obesity also reduce the growing socioeconomic and racial/ethnic inequities in its prevalence? Based on a review of existing initiatives in London and New York City, the Collaborative recommended 11 broad strategies by which each city could reduce childhood obesity. These recommendations were selected because they can be enacted at the municipal level; will reduce socioeconomic and racial/ethnic inequalities in obesity; are either well supported by research or are already being implemented in one city, demonstrating their feasibility; build on existing city assets; and are both green and healthy.
doi:10.1007/s11524-010-9493-x
PMCID: PMC2937123  PMID: 20811951
Childhood obesity; Municipal governance; Health inequities; Urban health
24.  A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers 
BMC Genomics  2012;13:341.
Background
Next generation sequencing (NGS) technology has revolutionized genomic and genetic research. The pace of change in this area is rapid with three major new sequencing platforms having been released in 2011: Ion Torrent’s PGM, Pacific Biosciences’ RS and the Illumina MiSeq. Here we compare the results obtained with those platforms to the performance of the Illumina HiSeq, the current market leader. In order to compare these platforms, and get sufficient coverage depth to allow meaningful analysis, we have sequenced a set of 4 microbial genomes with mean GC content ranging from 19.3 to 67.7%. Together, these represent a comprehensive range of genome content. Here we report our analysis of that sequence data in terms of coverage distribution, bias, GC distribution, variant detection and accuracy.
Results
Sequence generated by Ion Torrent, MiSeq and Pacific Biosciences technologies displays near perfect coverage behaviour on GC-rich, neutral and moderately AT-rich genomes, but a profound bias was observed upon sequencing the extremely AT-rich genome of Plasmodium falciparum on the PGM, resulting in no coverage for approximately 30% of the genome. We analysed the ability to call variants from each platform and found that we could call slightly more variants from Ion Torrent data compared to MiSeq data, but at the expense of a higher false positive rate. Variant calling from Pacific Biosciences data was possible but higher coverage depth was required. Context specific errors were observed in both PGM and MiSeq data, but not in that from the Pacific Biosciences platform.
Conclusions
All three fast turnaround sequencers evaluated here were able to generate usable sequence. However there are key differences between the quality of that data and the applications it will support.
doi:10.1186/1471-2164-13-341
PMCID: PMC3431227  PMID: 22827831
Next-generation sequencing; Ion torrent; Illumina; Pacific biosciences; MiSeq; PGM; SMRT; Bias; Genome coverage; GC-rich; AT-rich
25.  Bureaucracy stifles medical research in Britain: a tale of three trials 
Background
Recent developments aiming to standardise and streamline processes of gaining the necessary approvals to carry out research in the National Health Service (NHS) in the United Kingdom (UK), have resulted in lengthy and costly delays. The national UK governmental Department of Health’s Research Governance Framework (RGF) for Health and Social Care requires that appropriate checks be conducted before research involving human participants, their organs, tissues or data can commence in the NHS. As a result, medical research has been subjected to increased regulation and governance, with the requirement for approvals from numerous regulatory and monitoring bodies. In addition, the processes and outcomes of the attribution of costs in NHS research have caused additional difficulties for researchers. The purpose of this paper is to illustrate, through three trial case studies, the difficulties encountered during the set-up and recruitment phases of these trials, related to gaining the necessary ethical and governance approvals and applying for NHS costs to undertake and deliver the research.
Methods
Empirical evidence about delays and difficulties related to regulation and governance of medical research was gathered during the period 2009–2010 from three UK randomised controlled trials with sites in England, Wales and Scotland (1. SAFER 2- an emergency care based trial of a protocol for paramedics to refer patients directly to community based falls services; 2. COnStRUCT- a trial of two drugs for acute ulcerative colitis; and 3. Family Links - a trial of a public health intervention, a 10 week community based parenting programme). Findings and recommendations were reported in response to a call for evidence from The Academy of Medical Sciences regarding difficulties encountered in conducting medical research arising from R&D governance and regulation, to inform national policy.
Results
Difficulties and delays in navigating and gaining the appropriate approvals and NHS costs required to undertake the research were encountered in all three trials, at various points in the bureaucratic processes of ethical and research and information governance approvals. Conduct of each of the three trials was delayed by at least 12 months, with costs increasing by 30 – 40%.
Conclusions
Whilst the three trials encountered a variety of challenges, there were common issues. The processes for gaining approvals were overly complex and differed between sites and UK countries; guidance about processes was unclear; and information regarding how to define and claim NHS costs for undertaking the research was inconsistent. The competitive advantage of a publicly funded, open access health system for undertaking health services research and clinical trials within the UK has been outweighed in recent years by stifling bureaucratic structures and processes for governance of research. The recommendations of the Academy of Medical Sciences are welcomed, and the effects of their implementation are awaited with interest.
Trial Registration numbers
SAFER 2: ISRCTN 60481756; COnStRUCT: ISRCTN22663589; Family Links: ISRCTN 13929732
doi:10.1186/1471-2288-12-122
PMCID: PMC3537588  PMID: 22898336

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