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1.  Significance of HbA1c and its measurement in the diagnosis of diabetes mellitus: US experience 
The 2014 American Diabetes Association guidelines denote four means of diagnosing diabetes. The first of these is a glycosylated hemoglobin (HbA1c) >6.5%. This literature review summarizes studies (n=47) in the USA examining the significance, strengths, and limitations of using HbA1c as a diagnostic tool for diabetes, relative to other available means. Due to the relatively recent adoption of HbA1c as a diabetes mellitus diagnostic tool, a hybrid systematic, truncated review of the literature was implemented. Based on these studies, we conclude that HbA1c screening for diabetes has been found to be convenient and effective in diagnosing diabetes. HbA1c screening is particularly helpful in community-based and acute care settings where tests requiring fasting are not practical. Using HbA1c to diagnose diabetes also has some limitations. For instance, HbA1c testing may underestimate the prevalence of diabetes, particularly among whites. Because this bias differs by racial group, prevalence and resulting estimates of health disparities based on HbA1c screening differ from those based on other methods of diagnosis. In addition, existing evidence suggests that HbA1c screening may not be valid in certain subgroups, such as children, women with gestational diabetes, patients with human immunodeficiency virus, and those with prediabetes. Further guidelines are needed to clarify the appropriate use of HbA1c screening in these populations.
doi:10.2147/DMSO.S39092
PMCID: PMC4208352  PMID: 25349480
diabetes mellitus; diagnosis; glycosylated hemoglobin; USA
2.  First do no harm 
doi:10.3399/bjgp14X681733
PMCID: PMC4173708  PMID: 25267031
3.  Mutual Exclusivity of Hyaluronan and Hyaluronidase in Invasive Group A Streptococcus* 
The Journal of Biological Chemistry  2014;289(46):32303-32315.
Background: Serotype M4 group A Streptococcus lack hyaluronic acid (HA) capsule, but are capable of causing human disease.
Results: Encapsulation was achieved by introducing the hasABC capsule synthesis operon in the absence of HA-degrading enzyme hyaluronate lyase (HylA).
Conclusion: Capsule expression does not enhance M4 GAS virulence.
Significance: We demonstrate a mutually exclusive interaction between GAS capsule and HylA expression.
A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen.
doi:10.1074/jbc.M114.602847
PMCID: PMC4231703  PMID: 25266727
Bacterial Pathogenesis; Hyaluronan; Hyaluronate; Infectious Disease; Streptococcus Pyogenes (S. Pyogenes); Group A Streptococcus; Hyaluronate Lyase; Hyaluronic acid Capsule; Invasive Disease; Nonencapsulated
4.  The Impact of “Omic” and Imaging Technologies on Assessing the Host Immune Response to Biodefence Agents 
Journal of Immunology Research  2014;2014:237043.
Understanding the interactions between host and pathogen is important for the development and assessment of medical countermeasures to infectious agents, including potential biodefence pathogens such as Bacillus anthracis, Ebola virus, and Francisella tularensis. This review focuses on technological advances which allow this interaction to be studied in much greater detail. Namely, the use of “omic” technologies (next generation sequencing, DNA, and protein microarrays) for dissecting the underlying host response to infection at the molecular level; optical imaging techniques (flow cytometry and fluorescence microscopy) for assessing cellular responses to infection; and biophotonic imaging for visualising the infectious disease process. All of these technologies hold great promise for important breakthroughs in the rational development of vaccines and therapeutics for biodefence agents.
doi:10.1155/2014/237043
PMCID: PMC4182007  PMID: 25333059
5.  Food allergy training event for restaurant staff; a pilot evaluation 
A previous cross-sectional survey highlighted that restaurant staff in Brighton had gaps in their knowledge of food allergy, which could lead to the provision of unsafe meals to food-allergic customers. A food allergy training event was developed by a multi-disciplinary team (health service researcher, clinician, teacher and patient group representative) to equip restaurant staff with the knowledge and skills necessary to safely serve food-allergic customers. This evaluation summarises the training event’s impact on participants’ knowledge of food allergy and their satisfaction with the event.
No attendee had previously attended any formal training on food allergy. The percentage of participants who answered all true-false questions correctly increased from 82% before the training event to 91% afterwards. The percentage of participants who were able to name at least three common allergens increased from 9% to 64%. Both quantitative and qualitative feedback was positive.
Restaurant staff require a good understanding of food allergy to ensure that food-allergic customers are kept safe, and their restaurants operate within the law. This food allergy training event improved participants’ absolute knowledge of food allergy, and attendees changed practice. Recommendations are made which could improve the impact and uptake of future food allergy training events.
doi:10.1186/2045-7022-4-26
PMCID: PMC4164327  PMID: 25225607
Food allergy; Restaurant staff; Knowledge
6.  To see or not to see: a qualitative interview study of patients’ views on their own diagnostic images 
BMJ Open  2014;4(7):e004999.
Objectives
To ascertain what meaning individuals attach to perceiving images of their own interior body and how the images and their meanings affect the clinical consultation.
Design
Face-to-face semistructured interviews.
Participants
25 adult patients in southern England who, within the preceding 12 months, had been referred for diagnostic imaging.
Setting
Community.
Results
For patients, being shown their own X-rays, MRIs or CT images creates a variety of effects: (1) a sense of better understanding of the diagnosis; (2) validation of their sensory and emotional response to the illness or injury and (3) an alteration to the tenor and nature of the clinical encounter between patient and physician. In addition to meanings attached to these images, patients also impute meaning to the physician's decision not to share an image with them. The desire to see their image was greater in those patients with a skeletal injury; patients are less keen on viewing abdominal or other soft tissue images.
Conclusions
Viewing images of one's interior, invisible body is powerful and resonant in a number of ways. The experience of not seeing, whether through the patient's or the physician's choice, is also fraught with meaning.
doi:10.1136/bmjopen-2014-004999
PMCID: PMC4120403  PMID: 25082418
Primary Care; Qualitative Research
7.  Measurement properties of asthma-specific quality-of-life measures: protocol for a systematic review 
Systematic Reviews  2014;3:83.
Background
Asthma is a frequent chronic inflammatory disease of the airways, and the assessment of health-related quality of life (HrQoL) is important in both research and routine care. Various asthma-specific measures of HrQoL exist but there is uncertainty which measures are best suited for use in research and routine care. Therefore, the aim of the proposed research is a comprehensive systematic assessment of the measurement properties of the existing measures that were developed to measure asthma-specific quality of life.
Methods/design
This study is a systematic review of the measurement properties of asthma-specific measures of health-related quality of life. PubMed and Embase will be searched using a selection of relevant search terms. Eligible studies will be primary empirical studies evaluating, describing or comparing measurement properties of asthma-specific HRQL tools. Eligibility assessment and data abstraction will be performed independently by two reviewers. Evidence tables will be generated for study characteristics, instrument characteristics, measurement properties and interpretability. The quality of the measurement properties will be assessed using predefined criteria. Methodological quality of studies will be assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis will be undertaken if more than one study have investigated a particular measurement property.
Discussion
The proposed systematic review will produce a comprehensive assessment of measurement properties of existing measures of asthma-specific health-related quality of life. We also aim to derive recommendations in order to help researchers and practitioners alike in the choice of instrument.
Trial registration
PROSPERO registration number: CRD42014010491.
doi:10.1186/2046-4053-3-83
PMCID: PMC4124509  PMID: 25060719
Asthma; Health-related quality of life; Validity; Reliability; Responsiveness to change
8.  Cytomegalovirus infection modulates the phenotype and functional profile of the T-cell immune response to mycobacterial antigens in older life☆ 
Experimental Gerontology  2014;54(100):94-100.
Infection with Cytomegalovirus is associated with accelerated immunosenescence. Expansions of CMV-specific T cell responses have previously been demonstrated to affect the ability of T cells to respond to other infections. Most people above 60 years of age display M. tuberculosis-specific immunity because of vaccination, exposure, or both. T-cell responses can be assessed by measuring intracellular IFN-γ in vitro after tuberculin stimulation. Here we investigated tuberculin-specific CD4 T-cell responses in independently living healthy older people in the South of England using flow-cytometry. Individuals were investigated for tuberculin and CMV-specific T-cell immunity using in vitro antigen stimulation followed by intracellular staining for IFN-γ, TNF-α, IL2, as well as degranulation and CD154 upregulation. We also examined a control group of younger individuals (20–35 years of age). There was no significant difference between older and young people in regards to tuberculin responsiveness of CD4 T-cells; however, older people seemed to show more outliers. Increased responsiveness to tuberculin was significantly correlated to CMV responsiveness but not age. In older donors, the memory phenotype of tuberculin-induced T-cells was significantly skewed towards a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals and the degree of skewing correlated quantitatively with the size of the CMV-specific CD4 T-cell response. This is a fundamental advance over previous reports of changes of the tuberculin-specific CD4 T-cell response with CMV serostatus. Our results show that how the immune system responds to CMV has a fundamental impact on the phenotype and function of the immune response to mycobacterial antigens in older life.
Highlights
•We examine the CD4 T-cell response to tuberculosis antigens in older people.•The CD4 T-cell response to Cytomegalovirus is explored in parallel.•CMV infection changes the profile of the tuberculin-specific-response.•The size of the CMV T-cell response is linked to these changes in a quantitative way.•The way we respond to CMV (‘mode’) affects our T-cell immunity to other pathogens.
doi:10.1016/j.exger.2013.12.007
PMCID: PMC4003347  PMID: 24370373
Cytomegalovirus; Tuberculosis; Immunosenescence; T-cell response; Flow-cytometry
9.  A Systematic Approach to Capacity Strengthening of Laboratory Systems for Control of Neglected Tropical Diseases in Ghana, Kenya, Malawi and Sri Lanka 
Background
The lack of capacity in laboratory systems is a major barrier to achieving the aims of the London Declaration (2012) on neglected tropical diseases (NTDs). To counter this, capacity strengthening initiatives have been carried out in NTD laboratories worldwide. Many of these initiatives focus on individuals' skills or institutional processes and structures ignoring the crucial interactions between the laboratory and the wider national and international context. Furthermore, rigorous methods to assess these initiatives once they have been implemented are scarce. To address these gaps we developed a set of assessment and monitoring tools that can be used to determine the capacities required and achieved by laboratory systems at the individual, organizational, and national/international levels to support the control of NTDs.
Methodology and principal findings
We developed a set of qualitative and quantitative assessment and monitoring tools based on published evidence on optimal laboratory capacity. We implemented the tools with laboratory managers in Ghana, Malawi, Kenya, and Sri Lanka. Using the tools enabled us to identify strengths and gaps in the laboratory systems from the following perspectives: laboratory quality benchmarked against ISO 15189 standards, the potential for the laboratories to provide support to national and regional NTD control programmes, and the laboratory's position within relevant national and international networks and collaborations.
Conclusion
We have developed a set of mixed methods assessment and monitoring tools based on evidence derived from the components needed to strengthen the capacity of laboratory systems to control NTDs. Our tools help to systematically assess and monitor individual, organizational, and wider system level capacity of laboratory systems for NTD control and can be applied in different country contexts.
Author Summary
Capacity strengthening activities such as technical training for staff, student research project supervision, and equipment provision are being carried out in laboratories worldwide as part of the global effort to control neglected tropical diseases (NTDs). However, these activities often focus on developing the skill sets of an individual and are not being thoroughly monitored and assessed. To address these gaps we developed a set of monitoring and assessment tools that can be used to determine the capacities required and achieved by laboratory systems to support the control of NTDs. The tools simultaneously focus on individuals (e.g., technicians, students, researchers), organisations (e.g., universities, research institutions, clinical facilities), national governments, and international agencies. Using the tools highlighted the strengths and limitations of each laboratory system in addition to the role of the laboratory regionally and internationally. We used the tools in Kenya, Ghana, Malawi and Sri Lanka, and concluded that our tools can be adapted and tailored to use in other countries and laboratories.
doi:10.1371/journal.pntd.0002736
PMCID: PMC3945753  PMID: 24603407
10.  A practical and systematic approach to organisational capacity strengthening for research in the health sector in Africa 
Background
Despite increasing investment in health research capacity strengthening efforts in low and middle income countries, published evidence to guide the systematic design and monitoring of such interventions is very limited. Systematic processes are important to underpin capacity strengthening interventions because they provide stepwise guidance and allow for continual improvement. Our objective here was to use evidence to inform the design of a replicable but flexible process to guide health research capacity strengthening that could be customized for different contexts, and to provide a framework for planning, collecting information, making decisions, and improving performance.
Methods
We used peer-reviewed and grey literature to develop a five-step pathway for designing and evaluating health research capacity strengthening programmes, tested in a variety of contexts in Africa. The five steps are: i) defining the goal of the capacity strengthening effort, ii) describing the optimal capacity needed to achieve the goal, iii) determining the existing capacity gaps compared to the optimum, iv) devising an action plan to fill the gaps and associated indicators of change, and v) adapting the plan and indicators as the programme matures. Our paper describes three contrasting case studies of organisational research capacity strengthening to illustrate how our five-step approach works in practice.
Results
Our five-step pathway starts with a clear goal and objectives, making explicit the capacity required to achieve the goal. Strategies for promoting sustainability are agreed with partners and incorporated from the outset. Our pathway for designing capacity strengthening programmes focuses not only on technical, managerial, and financial processes within organisations, but also on the individuals within organisations and the wider system within which organisations are coordinated, financed, and managed.
Conclusions
Our five-step approach is flexible enough to generate and utilise ongoing learning. We have tested and critiqued our approach in a variety of organisational settings in the health sector in sub-Saharan Africa, but it needs to be applied and evaluated in other sectors and continents to determine the extent of transferability.
doi:10.1186/1478-4505-12-11
PMCID: PMC3975897  PMID: 24581148
Africa; Capacity building; Capacity development; Health systems; Organisational capacity; Organisational capacity development; Research capacity strengthening
11.  Reliability of a New Stabilized Dynamometer System for the Evaluation of Hip Strength 
Sports Health  2013;5(2):129-136.
Background:
Hip strength is associated with numerous orthopaedic and neuromuscular injuries and/or pathologies and may be assessed with a variety of anatomic testing positions and techniques. Isokinetic dynamometers are generally too cumbersome and intricate for efficient use in mass screenings (for prognostic studies of risk for injury) as well as with special populations. The reliability of isometric testing devices has demonstrated varied reliability, generally examining only 1 or 2 motions of the hip and reporting values of force, not torque. Consequently, there is a need for an efficient hip strength-testing device to quantify torque that tests subjects in 1 anatomic position, while evaluating multiple hip motions.
Hypothesis:
Evaluation of supine hip abduction, adduction, flexion, and extension torque using a new stabilized dynamometer system will produce good to excellent intra- and interexaminer reliability results.
Study Design:
A blinded, randomized, repeated-measures study design was used in this descriptive laboratory investigation.
Methods:
Supine isometric hip flexion, extension, abduction, and adduction torques were evaluated with a cage-stabilized dynamometer in 19 collegiate and professional-level ice hockey athletes by 2 investigators at 3 time intervals. Inter- and intrarater reliability was assessed.
Results:
Supine hip flexion, extension, abduction, and adduction torque was performed with good to excellent inter- and intrarater reliability (intraclass correlation coefficients ranging from 0.74 to 0.92 and 0.78 to 0.92, respectively) for all motions tested.
Conclusions:
We have developed an isometric hip strength-testing device that can be assembled around an examination table to efficiently and reliably evaluate torque developed for multiple motions of the hip.
Clinical Relevance:
This device and testing protocol may be used to efficiently evaluate hip strength in numerous settings; it allows decreased subject burden and increased comfort (which may be important following an injury in case-control investigations); and it may be well tolerated when testing athletes as well as special populations in the clinical setting.
doi:10.1177/1941738112459486
PMCID: PMC3658376  PMID: 24427380
isometric; hip joint; strength testing; dynamometry; torque
12.  Multilocus Genotype Analysis of Escherichia coli O157 Isolates from Australia and the United States Provides Evidence of Geographic Divergence 
Applied and Environmental Microbiology  2013;79(16):5050-5058.
Escherichia coli O157 is a food-borne pathogen whose major reservoir has been identified as cattle. Recent genetic information has indicated that populations of E. coli O157 from cattle and humans can differ genetically and that this variation may have an impact on their ability to cause severe human disease. In addition, there is emerging evidence that E. coli O157 strains from different geographical regions may also be genetically divergent. To investigate the extent of this variation, we used Shiga toxin bacteriophage insertion sites (SBI), lineage-specific polymorphisms (LSPA-6), multilocus variable-number tandem-repeat analysis (MLVA), and a tir 255T>A polymorphism to examine 606 isolates representing both Australian and U.S. cattle and human populations. Both uni- and multivariate analyses of these data show a strong association between the country of origin and multilocus genotypes (P < 0.0001). In addition, our results identify factors that may play a role in virulence that also differed in isolates from each country, including the carriage of stx1 in the argW locus uniquely observed in Australian isolates and the much higher frequency of stx2-positive (also referred to as stx2a) strains in the U.S. isolates (4% of Australian isolates versus 72% of U.S. isolates). LSPA-6 lineages differed between the two continents, with the majority of Australian isolates belonging to lineage I/II (LI/II) (LI, 2%; LI/II, 85%; LII, 13%) and the majority of U.S. isolates belonging to LI (LI, 60%; LI/II, 16%; LII, 25%). The results of this study provide strong evidence of phylogeographic structuring of E. coli O157 populations, suggesting divergent evolution of enterohemorrhagic E. coli O157 in Australia and the United States.
doi:10.1128/AEM.01525-13
PMCID: PMC3754714  PMID: 23770913
13.  Community Acceptance of Tsetse Control Baits: A Qualitative Study in Arua District, North West Uganda 
Background
There is renewed vigour in efforts to eliminate neglected tropical diseases including sleeping sickness (human African trypanosomiasis or HAT), including attempts to develop more cost-effective methods of tsetse control. In the West Nile region of Uganda, newly designed insecticide-treated targets are being deployed over an area of ∼500 km2. The operational area covers villages where tsetse control has not been conducted previously. The effectiveness of the targets will depend, in part, on their acceptance by the local community.
Methodology/Principal Findings
We assessed knowledge, perceptions and acceptance of tsetse baits (traps, targets) in villages where they had or had not been used previously. We conducted sixteen focus group discussions with male and female participants in eight villages across Arua District. Discussions were audio recorded, translated and transcribed. We used thematic analysis to compare the views of both groups and identify salient themes.
Conclusions/Significance
Despite the villages being less than 10 km apart, community members perceived deployed baits very differently. Villagers who had never seen traps before expressed fear, anxiety and panic when they first encountered them. This was related to associations with witchcraft and “ghosts from the river” which are traditionally linked with physical or mental illness, death and misfortune. By contrast, villagers living in areas where traps had been used previously had positive attitudes towards them and were fully aware of their purpose and benefits. The latter group reported that they had similar negative perceptions when tsetse control interventions first started a decade ago. Our results suggest that despite their proximity, acceptance of traps varies markedly between villages and this is related to the duration of experience with tsetse control programs. The success of community-based interventions against tsetse will therefore depend on early engagements with communities and carefully designed sensitization campaigns that reach all communities, especially those living in areas new to such interventions.
Author Summary
Sleeping sickness is a disease which results in serious physical and mental symptoms and is ultimately deadly if not treated. It is caused by sub-species of Trypanosoma brucei transmitted by tsetse which live exclusively in Africa. Currently, the only preventive measure against sleeping sickness is reduction of tsetse population in the areas where these flies and humans share the same living space. This can be achieved through the use of traps or insecticide-treated targets to attract and kill tsetse. As the traps are newly introduced in some areas, we explored how local communities perceive them. We compared their views to those of communities living in areas where traps have been used sporadically for more than 10 years. Despite villages with or without experience of vector control being less than 10 km apart, they had very different perceptions: the group new to targets had many negative perceptions, associated with witchcraft and supernatural powers, while the group knowing targets from the past perceived them positively and beneficial. Understanding of local perceptions is important, because it will help us to involve communities affected by sleeping sickness in tsetse control programs. Without their support these programs are short-lived and ineffective.
doi:10.1371/journal.pntd.0002579
PMCID: PMC3861179  PMID: 24349593
14.  A Novel Cytomegalovirus-Induced Regulatory-Type T-Cell Subset Increases in Size During Older Life and Links Virus-Specific Immunity to Vascular Pathology 
The Journal of Infectious Diseases  2013;209(9):1382-1392.
Background. Cytomegalovirus (CMV) infection directly targets vascular endothelium and smooth muscle and at older ages is associated with accelerated vascular pathology and mortality. CMV-specific cellular immunity might directly contribute to this process.
Methods. Conventional ex vivo activation–induced T-cell responses to 19 dominant CMV antigens, along with CMV-specific inducible regulatory-type CD4+ T cells (iTregs), were measured in healthy older people, using a novel protocol that included classic Treg markers alongside the activation marker CD134. Measurements were correlated with diastolic, systolic, and mean arterial blood pressure, a surrogate marker for arterial stiffness.
Results. CMV-specific iTregs recognized the same antigens as conventional CD4+ T cells and were significantly more frequent at older ages. They suppressed antigen-specific and nonspecific proliferation and in large part expressed Foxp3. Frequencies of CMV-specific iTregs and CD8+ T cells (summated response) were significantly associated with diastolic and mean arterial pressures. Confounders, including age, body mass index, smoking, antihypertensive medication use, or C-reactive protein levels, did not explain these observations.
Conclusions. A novel CMV-induced regulatory-type CD4+ T-cell subset is readily detectable in CMV-infected people and, like the aggregate CD8+ T-cell response to the most dominant CMV antigens, is quantitatively associated with arterial stiffness in older life. Whereas CD8+ effector T cells might directly cause vascular injury, iTregs may attenuate this response.
doi:10.1093/infdis/jit576
PMCID: PMC3982844  PMID: 24203779
Arteriosclerosis; infection; immunology; inflammation; hypertension; iTreg; Regulatory T-Cells
15.  Correction: World Health Organization Guideline Development: An Evaluation 
PLoS ONE  2013;8(9):10.1371/annotation/fd04e7c6-0d40-4d2c-a382-c5ad10074c99.
doi:10.1371/annotation/fd04e7c6-0d40-4d2c-a382-c5ad10074c99
PMCID: PMC3779259
16.  Surveillance of pneumococcal serotype 1 carriage during an outbreak of serotype 1 invasive pneumococcal disease in central Australia 2010–2012 
BMC Infectious Diseases  2013;13:409.
Background
An outbreak of serotype 1 invasive pneumococcal disease (IPD) occurred in Central Australia from October 2010 to the latter part of 2012. Surveillance of serotype 1 carriage was conducted to determine epidemiological features of asymptomatic carriage that could potentially be driving the outbreak.
Methods
130 patients and accompanying persons presenting at Alice Springs Hospital Emergency Department consented to nasopharyngeal swab (NPS) collection. NPS were processed by standard methods, including culture, pneumococcal lytA quantitative real-time PCR, serotype 1-specific real-time PCR and multi-locus sequence typing (MLST).
Results
Pneumococcal carriage was detected in 16% of participants. Carriage was highest in the under 10 year olds from remote communities surrounding Alice Springs (75%). Four NPS were positive for serotype 1 DNA by PCR; 3 were also culture-positive for serotype 1 pneumococci. Serotype 1 isolates had atypical colony morphology on primary culture. All serotype 1 carriers were healthy children 5 to 8 years of age from remote communities. By MLST, serotype 1 isolates were ST306, as were IPD isolates associated with this outbreak.
Conclusions
During an outbreak of serotype 1 ST306 IPD, carriage of the outbreak strain was detected in 3% NPS collected. All carriers were healthy children 5 to 8 years of age.
doi:10.1186/1471-2334-13-409
PMCID: PMC3766201  PMID: 24138669
Invasive pneumococcal disease; Serotype 1; Central Australia; Carriage
17.  Maintenance of Interphase Chromosome Compaction and Homolog Pairing in Drosophila Is Regulated by the Condensin Cap-H2 and Its Partner Mrg15 
Genetics  2013;195(1):127-146.
Dynamic regulation of chromosome structure and organization is critical for fundamental cellular processes such as gene expression and chromosome segregation. Condensins are conserved chromosome-associated proteins that regulate a variety of chromosome dynamics, including axial shortening, lateral compaction, and homolog pairing. However, how the in vivo activities of condensins are regulated and how functional interactors target condensins to chromatin are not well understood. To better understand how Drosophila melanogaster condensin is regulated, we performed a yeast two-hybrid screen and identified the chromo-barrel domain protein Mrg15 to interact with the Cap-H2 condensin subunit. Genetic interactions demonstrate that Mrg15 function is required for Cap-H2-mediated unpairing of polytene chromosomes in ovarian nurse cells and salivary gland cells. In diploid tissues, transvection assays demonstrate that Mrg15 inhibits transvection at Ubx and cooperates with Cap-H2 to antagonize transvection at yellow. In cultured cells, we show that levels of chromatin-bound Cap-H2 protein are partially dependent on Mrg15 and that Cap-H2-mediated homolog unpairing is suppressed by RNA interference depletion of Mrg15. Thus, maintenance of interphase chromosome compaction and homolog pairing status requires both Mrg15 and Cap-H2. We propose a model where the Mrg15 and Cap-H2 protein–protein interaction may serve to recruit Cap-H2 to chromatin and facilitates compaction of interphase chromatin.
doi:10.1534/genetics.113.153544
PMCID: PMC3761296  PMID: 23821596
condensin; homolog pairing; Mrg15; chromosome structure; transvection
18.  Optimising the use of electronic health records to estimate the incidence of rheumatoid arthritis in primary care: what information is hidden in free text? 
Background
Primary care databases are a major source of data for epidemiological and health services research. However, most studies are based on coded information, ignoring information stored in free text. Using the early presentation of rheumatoid arthritis (RA) as an exemplar, our objective was to estimate the extent of data hidden within free text, using a keyword search.
Methods
We examined the electronic health records (EHRs) of 6,387 patients from the UK, aged 30 years and older, with a first coded diagnosis of RA between 2005 and 2008. We listed indicators for RA which were present in coded format and ran keyword searches for similar information held in free text. The frequency of indicator code groups and keywords from one year before to 14 days after RA diagnosis were compared, and temporal relationships examined.
Results
One or more keyword for RA was found in the free text in 29% of patients prior to the RA diagnostic code. Keywords for inflammatory arthritis diagnoses were present for 14% of patients whereas only 11% had a diagnostic code. Codes for synovitis were found in 3% of patients, but keywords were identified in an additional 17%. In 13% of patients there was evidence of a positive rheumatoid factor test in text only, uncoded. No gender differences were found. Keywords generally occurred close in time to the coded diagnosis of rheumatoid arthritis. They were often found under codes indicating letters and communications.
Conclusions
Potential cases may be missed or wrongly dated when coded data alone are used to identify patients with RA, as diagnostic suspicions are frequently confined to text. The use of EHRs to create disease registers or assess quality of care will be misleading if free text information is not taken into account. Methods to facilitate the automated processing of text need to be developed and implemented.
doi:10.1186/1471-2288-13-105
PMCID: PMC3765394  PMID: 23964710
Electronic health records; Electronic medical records; Rheumatoid arthritis; Free text; Coding
19.  Impact of a referral management “gateway” on the quality of referral letters; a retrospective time series cross sectional review 
Background
Referral management centres (RMC) for elective referrals are designed to facilitate the primary to secondary care referral path, by improving quality of referrals and easing pressures on finite secondary care services, without inadvertently compromising patient care.
This study aimed to evaluate whether the introduction of a RMC which includes triage and feedback improved the quality of elective outpatient referral letters.
Methods
Retrospective, time-series, cross-sectional review involving 47 general practices in one primary care trust (PCT) in South-East England. Comparison of a random sample of referral letters at baseline (n = 301) and after seven months of referral management (n = 280). Letters were assessed for inclusion of four core pieces of information which are used locally to monitor referral quality (blood pressure, body mass index, past medical history, medication history) and against research-based quality criteria for referral letters (provision of clinical information and clarity of reason for referral).
Results
Following introduction of the RMC, the proportion of letters containing each of the core items increased compared to baseline. Statistically significant increases in the recording of ‘past medical history’ (from 71% to 84%, p < 0.001) and ‘medication history’ (78% to 87%, p = 0.006) were observed. Forty four percent of letters met the research-based quality criteria at baseline but there was no significant change in quality of referral letters judged on these criteria across the two time periods.
Conclusion
Introduction of RMC has improved the inclusion of past medical history and medication history in referral letters, but not other measures of quality. In approximately half of letters there remains room for further improvement.
doi:10.1186/1472-6963-13-310
PMCID: PMC3844396  PMID: 23945378
General practice; Referral letters; Quality improvement; Peer review; Referral management
20.  Factors Affecting the Delivery, Access, and Use of Interventions to Prevent Malaria in Pregnancy in Sub-Saharan Africa: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(7):e1001488.
Jenny Hill and colleagues conduct a systematic review and meta-analysis of qualitative, quantitative, and mixed methods studies to explore the factors that affect the delivery, access, and use of interventions to prevent malaria in pregnant women in sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Malaria in pregnancy has important consequences for mother and baby. Coverage with the World Health Organization–recommended prevention strategy for pregnant women in sub-Saharan Africa of intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated nets (ITNs) is low. We conducted a systematic review to explore factors affecting delivery, access, and use of IPTp and ITNs among healthcare providers and women.
Methods and Results
We searched the Malaria in Pregnancy Library and Global Health Database from 1 January 1990 to 23 April 2013, without language restriction. Data extraction was performed by two investigators independently, and data was appraised for quality and content. Data on barriers and facilitators, and the effect of interventions, were explored using content analysis and narrative synthesis. We conducted a meta-analysis of determinants of IPTp and ITN uptake using random effects models, and performed subgroup analysis to evaluate consistency across interventions and study populations, countries, and enrolment sites. We did not perform a meta-ethnography of qualitative data.
Ninety-eight articles were included, of which 20 were intervention studies. Key barriers to the provision of IPTp and ITNs were unclear policy and guidance on IPTp; general healthcare system issues, such as stockouts and user fees; health facility issues stemming from poor organisation, leading to poor quality of care; poor healthcare provider performance, including confusion over the timing of each IPTp dose; and women's poor antenatal attendance, affecting IPTp uptake. Key determinants of IPTp coverage were education, knowledge about malaria/IPTp, socio-economic status, parity, and number and timing of antenatal clinic visits. Key determinants of ITN coverage were employment status, education, knowledge about malaria/ITNs, age, and marital status. Predictors showed regional variations.
Conclusions
Delivery of ITNs through antenatal clinics presents fewer problems than delivery of IPTp. Many obstacles to IPTp delivery are relatively simple barriers that could be resolved in the short term. Other barriers are more entrenched within the overall healthcare system or socio-economic/cultural contexts, and will require medium- to long-term strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Half the world's population is at risk of malaria, a mosquito-borne parasite that kills a million people every year. Most of these deaths occur among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also vulnerable to malaria. Infection with malaria during pregnancy can cause maternal death, severe maternal anemia, miscarriages, and pre-term and low-birth-weight babies. Malaria in pregnancy is responsible for about 100,000 babies and 10,000 women dying every year but is preventable by simple, inexpensive interventions that have been available for many years. The World Health Organization recommends a three-pronged approach to the prevention of malaria in pregnancy in areas with stable malaria transmission in Africa—delivery of the antimalarial drug sulfadoxine-pyrimethamine to pregnant women during antenatal clinic visits (intermittent preventative treatment in pregnancy; IPTp), the use of insecticide-treated bed nets (ITNs) to protect pregnant women from the bites of infected mosquitoes, and effective diagnosis and case management of pregnant women with malarial illness.
Why Was This Study Done?
Coverage with this prevention strategy is currently very low. Recent survey data from sub-Saharan African countries suggest that only about a quarter of pregnant women receive two doses of IPTp and only about a third use ITNs. To improve coverage, public health experts need to understand why coverage is so low, and they need to know the factors (determinants) that are associated with the uptake of IPTp and ITNs. In this systematic review and meta-analysis of qualitative, quantitative, and mixed methods studies, the researchers explore the factors that affect delivery, access, and use of IPTp and ITNs among pregnant women in sub-Saharan Africa. A systematic review uses predefined criteria to identify all the research on a given topic. Meta-analysis is a statistical method for combining the results of several studies. Qualitative studies collect non-quantitative data such as reasons for not accepting an intervention, whereas quantitative studies collect numerical data such as the proportion of a population accepting an intervention.
What Did the Researchers Do and Find?
The researchers' search of the Malaria in Pregnancy Library (a resource maintained by the Malaria in Pregnancy Consortium) and the Global Health Database identified 98 studies that provided data on barriers to and determinants of IPTp and ITN uptake and/or data on interventions designed to increase IPTp and ITN uptake. The researchers explored these data using content analysis (a research methodology that examines words and phrases within texts) and narrative synthesis (a method for summarizing results drawn from several qualitative studies). Key barriers to the provision and uptake of IPTp and ITNs included unclear policy and guidance on IPTp, general healthcare system issues such as drug shortages, healthcare facility issues such as unavailability of water for the provision of IPTp by directly observed therapy, poor healthcare provider performance such as confusion about the timing of IPTp doses, and the delayed antenatal care-seeking practices of pregnant women. The researchers' meta-analysis identified education, knowledge about malaria, socio-economic status, number and timing of antenatal clinic visits, and number of pregnancies as key determinants of IPTp uptake, and employment status, education, knowledge, age, and marital status as key determinants of coverage of ITN use. So, for example, highly educated women were more likely to receive IPTp or ITNs than poorly educated women.
What Do These Findings Mean?
These findings identify key interacting barriers to access, delivery, and use of IPTp and ITNs in sub-Saharan Africa and show that these barriers are relatively consistent across countries. Moreover, they suggest that there are fewer barriers to the delivery of ITNs through antenatal clinics than to the delivery of IPTp. Importantly, some of the barriers to IPTp uptake can be resolved in the short term (for example, simplification of country policies and guidance on IPTp might increase its uptake), but barriers to uptake that are entrenched within the overall healthcare system will only be resolved with medium- to long-term strategies that aim to improve the quality of antenatal services and to encourage antenatal clinic use among women. Overall, this analysis provides a checklist of factors that policy-makers involved in national malaria programs may be able to use to help them decide which interventions to prioritize. However, the researchers warn, multi-country studies are nevertheless urgently needed to evaluate targeted or multifaceted interventions designed to increase delivery and uptake of IPTp and ITNs, to reduce the adverse consequences of malaria in pregnancy.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001488.
Information is available from the World Health Organization on malaria (in several languages) and on IPTp; the World Malaria Report 2012 provides details of the current global malaria situation
The US Centers for Disease Control and Prevention also provides information on malaria and on IPTp; a personal story about malaria in pregnancy is available
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001488
PMCID: PMC3720261  PMID: 23935459
21.  Sex While Intoxicated: A Meta-Analysis Comparing Heterosexual and Sexual Minority Youth 
Background
The social marginalization and victimization experienced by sexual minority youth (SMY) may lead to increased risk behaviors and higher rates of negative health outcomes compared with their heterosexual peers.
Methods
We conducted a meta-analysis to examine whether SMY reported higher rates of sex while intoxicated. Studies that report rates of substance use during sex in both SMY and heterosexual youth and had a mean participant age of 18 or less were included in our meta-analysis. Effect sizes were extracted from six studies (nine independent data sets and 24 effect sizes) that met study criteria and had high inter-rater reliability (.98).
Results
Results indicated that SMY were almost twice as likely to report sex while intoxicated as compared with heterosexual peers. A random-effects meta-analysis showed a moderate ([overall weighted effect OR]= 1.91, p < .0001) weighted effect size for the relationship between sexual orientation and the use of drugs at the time of sexual intercourse, with the mean effect size for each study ranging from 1.21 to 3.50 and individual effect sizes ranging from .35 to 9.86.
Discussion
Our findings highlight the need for healthcare providers to screen SMY for participation in substance use during sexual intercourse and to offer risk reduction counseling during office visits.
doi:10.1016/j.jadohealth.2010.07.008
PMCID: PMC3691819  PMID: 21338904
LGBT health; Adolescent health; Health disparities; Adolescent sexual health
22.  World Health Organization Guideline Development: An Evaluation 
PLoS ONE  2013;8(5):e63715.
Background
Research in 2007 showed that World Health Organization (WHO) recommendations were largely based on expert opinion, rarely used systematic evidence-based methods, and did not follow the organization's own “Guidelines for Guidelines”. In response, the WHO established a “Guidelines Review Committee” (GRC) to implement and oversee internationally recognized standards. We examined the impact of these changes on WHO guideline documents and explored senior staff's perceptions of the new procedures.
Methods and Findings
We used the AGREE II guideline appraisal tool to appraise ten GRC-approved guidelines from nine WHO departments, and ten pre-GRC guidelines matched by department and topic. We interviewed 20 senior staff across 16 departments and analyzed the transcripts using the framework approach. Average AGREE II scores for GRC-approved guidelines were higher across all six AGREE domains compared with pre-GRC guidelines. The biggest changes were noted for “Rigour of Development” (up 37.6%, from 30.7% to 68.3%) and “Editorial Independence” (up 52.7%, from 20.9% to 73.6%). Four main themes emerged from the interviews: (1) high standards were widely recognized as essential for WHO credibility, particularly with regard to conflicts of interest; (2) views were mixed on whether WHO needed a single quality assurance mechanism, with some departments purposefully bypassing the procedures; (3) staff expressed some uncertainties in applying the GRADE approach, with departmental staff concentrating on technicalities while the GRC remained concerned the underlying principles were not fully institutionalized; (4) the capacity to implement the new standards varied widely, with many departments looking to an overstretched GRC for technical support.
Conclusions
Since 2007, WHO guideline development methods have become more systematic and transparent. However, some departments are bypassing the procedures, and as yet neither the GRC, nor the quality assurance standards they have set, are fully embedded within the organization.
doi:10.1371/journal.pone.0063715
PMCID: PMC3669321  PMID: 23741299
24.  Trajectories of Alcohol and Cigarette Use among Sexual Minority and Heterosexual Girls 
Purpose
To examine disparities between sexual minority girls (SMGs) and heterosexual girls in trajectories of substance use over time.
Method
Girls were included in the analyses if they were age 12–18 years old at Wave 1 and not missing sexual orientation data at Wave 4 (n=7765). Latent curve models were estimated across all 4 waves (extending from middle adolescence into young adulthood) to examine trajectories of cigarette and alcohol use.
Results
Initial levels of substance use were higher for SMGs than they were for heterosexual girls. SMGs also exhibited sharper escalations in use over time across all substances as they were transitioning into young adulthood.
Conclusions
Persistent rates of cigarette and heavy alcohol use among SMGs may increase their risk for a host of mental and physical health problems in adulthood. Clinicians should be prepared to discuss SMG health topics effectively and in private, and discuss prevention and intervention programs with girls at risk.
doi:10.1016/j.jadohealth.2011.05.008
PMCID: PMC3649138  PMID: 22188841
LGBT health; sexual minority girls; homosexuality; adolescent substance use; alcohol use; cigarette use; adolescent health disparities
25.  Risk Factors for Anterior Cruciate Ligament Injury 
Sports Health  2012;4(2):155-161.
Context:
Injuries to the anterior cruciate ligament (ACL) are immediately disabling and are associated with long-term consequences, such as posttraumatic osteoarthritis. It is important to have a comprehensive understanding of all possible risk factors for ACL injury to identify individuals who are at risk for future injuries and to provide an appropriate level of counseling and programs for prevention.
Objective:
This review, part 2 of a 2-part series, highlights what is known and still unknown regarding hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors for ACL injury.
Data Sources:
Studies were identified from MEDLINE (1951–March 2011) using the MeSH terms anterior cruciate ligament, knee injury, and risk factors. The bibliographies of relevant articles and reviews were cross-referenced to complete the search.
Study Selection:
Prognostic case-control and prospective cohort study designs to evaluate risk factors for ACL injury were included in this review.
Results:
A total of 50 case-control and prospective cohort articles were included in parts 1 and 2. Twenty-one focused on hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors.
Conclusions:
Several risk factors are associated with increased risk of suffering ACL injury—such as female sex, prior reconstruction of the ACL, and familial predisposition. These risk factors most likely act in combination with the anatomic factors reviewed in part 1 of this series to influence the risk of suffering ACL injury.
doi:10.1177/1941738111428282
PMCID: PMC3435909  PMID: 23016083
anterior cruciate ligament (ACL); knee injury; risk factors

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