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1.  A Systematic Approach to Capacity Strengthening of Laboratory Systems for Control of Neglected Tropical Diseases in Ghana, Kenya, Malawi and Sri Lanka 
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.
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.
PMCID: PMC3945753  PMID: 24603407
2.  A practical and systematic approach to organisational capacity strengthening for research in the health sector in Africa 
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.
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.
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.
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.
PMCID: PMC3975897  PMID: 24581148
Africa; Capacity building; Capacity development; Health systems; Organisational capacity; Organisational capacity development; Research capacity strengthening
3.  Reliability of a New Stabilized Dynamometer System for the Evaluation of Hip Strength 
Sports Health  2013;5(2):129-136.
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.
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.
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.
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.
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.
PMCID: PMC3658376  PMID: 24427380
isometric; hip joint; strength testing; dynamometry; torque
4.  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.
PMCID: PMC3754714  PMID: 23770913
5.  Community Acceptance of Tsetse Control Baits: A Qualitative Study in Arua District, North West Uganda 
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.
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.
PMCID: PMC3861179  PMID: 24349593
6.  Correction: World Health Organization Guideline Development: An Evaluation 
PLoS ONE  2013;8(9):10.1371/annotation/fd04e7c6-0d40-4d2c-a382-c5ad10074c99.
PMCID: PMC3779259  PMID: 24086194
7.  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.
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.
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).
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.
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.
PMCID: PMC3766201  PMID: 24138669
Invasive pneumococcal disease; Serotype 1; Central Australia; Carriage
8.  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.
PMCID: PMC3761296  PMID: 23821596
condensin; homolog pairing; Mrg15; chromosome structure; transvection
9.  Optimising the use of electronic health records to estimate the incidence of rheumatoid arthritis in primary care: what information is hidden in free text? 
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.
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.
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.
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.
PMCID: PMC3765394  PMID: 23964710
Electronic health records; Electronic medical records; Rheumatoid arthritis; Free text; Coding
10.  Impact of a referral management “gateway” on the quality of referral letters; a retrospective time series cross sectional review 
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.
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).
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.
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.
PMCID: PMC3844396  PMID: 23945378
General practice; Referral letters; Quality improvement; Peer review; Referral management
11.  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
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.
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
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
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)
PMCID: PMC3720261  PMID: 23935459
12.  Sex While Intoxicated: A Meta-Analysis Comparing Heterosexual and Sexual Minority Youth 
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.
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 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.
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.
PMCID: PMC3691819  PMID: 21338904
LGBT health; Adolescent health; Health disparities; Adolescent sexual health
13.  World Health Organization Guideline Development: An Evaluation 
PLoS ONE  2013;8(5):e63715.
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.
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.
PMCID: PMC3669321  PMID: 23741299
15.  Trajectories of Alcohol and Cigarette Use among Sexual Minority and Heterosexual Girls 
To examine disparities between sexual minority girls (SMGs) and heterosexual girls in trajectories of substance use over time.
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.
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.
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.
PMCID: PMC3649138  PMID: 22188841
LGBT health; sexual minority girls; homosexuality; adolescent substance use; alcohol use; cigarette use; adolescent health disparities
16.  Risk Factors for Anterior Cruciate Ligament Injury 
Sports Health  2012;4(2):155-161.
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.
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.
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.
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.
PMCID: PMC3435909  PMID: 23016083
anterior cruciate ligament (ACL); knee injury; risk factors
17.  Optimising Use of Electronic Health Records to Describe the Presentation of Rheumatoid Arthritis in Primary Care: A Strategy for Developing Code Lists 
PLoS ONE  2013;8(2):e54878.
Research using electronic health records (EHRs) relies heavily on coded clinical data. Due to variation in coding practices, it can be difficult to aggregate the codes for a condition in order to define cases. This paper describes a methodology to develop ‘indicator markers’ found in patients with early rheumatoid arthritis (RA); these are a broader range of codes which may allow a probabilistic case definition to use in cases where no diagnostic code is yet recorded.
We examined EHRs of 5,843 patients in the General Practice Research Database, aged ≥30y, with a first coded diagnosis of RA between 2005 and 2008. Lists of indicator markers for RA were developed initially by panels of clinicians drawing up code-lists and then modified based on scrutiny of available data. The prevalence of indicator markers, and their temporal relationship to RA codes, was examined in patients from 3y before to 14d after recorded RA diagnosis.
Indicator markers were common throughout EHRs of RA patients, with 83.5% having 2 or more markers. 34% of patients received a disease-specific prescription before RA was coded; 42% had a referral to rheumatology, and 63% had a test for rheumatoid factor. 65% had at least one joint symptom or sign recorded and in 44% this was at least 6-months before recorded RA diagnosis.
Indicator markers of RA may be valuable for case definition in cases which do not yet have a diagnostic code. The clinical diagnosis of RA is likely to occur some months before it is coded, shown by markers frequently occurring ≥6 months before recorded diagnosis. It is difficult to differentiate delay in diagnosis from delay in recording. Information concealed in free text may be required for the accurate identification of patients and to assess the quality of care in general practice.
PMCID: PMC3579840  PMID: 23451024
18.  Altered Cohesin Gene Dosage Affects Mammalian Meiotic Chromosome Structure and Behavior 
PLoS Genetics  2013;9(2):e1003241.
Based on studies in mice and humans, cohesin loss from chromosomes during the period of protracted meiotic arrest appears to play a major role in chromosome segregation errors during female meiosis. In mice, mutations in meiosis-specific cohesin genes cause meiotic disturbances and infertility. However, the more clinically relevant situation, heterozygosity for mutations in these genes, has not been evaluated. We report here evidence from the mouse that partial loss of gene function for either Smc1b or Rec8 causes perturbations in the formation of the synaptonemal complex (SC) and affects both synapsis and recombination between homologs during meiotic prophase. Importantly, these defects increase the frequency of chromosomally abnormal eggs in the adult female. These findings have important implications for humans: they suggest that women who carry mutations or variants that affect cohesin function have an elevated risk of aneuploid pregnancies and may even be at increased risk of transmitting structural chromosome abnormalities.
Author Summary
Chromosome segregation errors during meiosis are the leading cause of birth defects and miscarriages in humans. While the basis for these errors is unknown, recent studies suggest that defective sister chromatid cohesion may be an important contributor. Accordingly, we tested the hypothesis that partial loss of gene function for either of two meiosis-specific cohesins, Smc1b or Rec8, might adversely affect synapsis or recombination between homologs during meiotic prophase. Our analyses of different mouse models demonstrate cohesin dosage effects on meiosis in both males and females. Importantly, reduced gene function led to an increase the frequency of chromosomally abnormal eggs in the adult female, suggesting that, in humans, women carrying cohesin mutations may be at an increased risk of chromosomally abnormal pregnancies.
PMCID: PMC3567145  PMID: 23408896
19.  Risk Factors for Anterior Cruciate Ligament Injury 
Sports Health  2012;4(1):69-78.
Injuries to the anterior cruciate ligament (ACL) of the knee are immediately debilitating and can cause long-term consequences, including the early onset of 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.
This review, part 1 of a 2-part series, highlights what is known and still unknown regarding anatomic and neuromuscular risk factors for injury to the ACL from the current peer-reviewed literature.
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 studies that utilized the case-control and prospective cohort study designs to evaluate risk factors for ACL injury were included in this review.
A total of 50 case-control and prospective cohort articles were included in the review, and 30 of these studies focused on neuromuscular and anatomic risk factors.
Several anatomic and neuromuscular risk factors are associated with increased risk of suffering ACL injury—such as female sex and specific measures of bony geometry of the knee joint, including decreased intercondylar femoral notch size, decreased depth of concavity of the medial tibial plateau, increased slope of the tibial plateaus, and increased anterior-posterior knee laxity. These risk factors most likely act in combination to influence the risk of ACL injury; however, multivariate risk models that consider all the aforementioned risk factors in combination have not been established to explore this interaction.
PMCID: PMC3435896  PMID: 23016072
Anterior Cruciate Ligament; knee injury; risk factors
20.  Increase in direct diabetes-related costs and resource use in the 6 months following initiation of insulin in patients with type 2 diabetes in five European countries: data from the INSTIGATE study 
The purpose of this study was to describe the resource use and associated direct costs of diabetes care for patients with type 2 diabetes mellitus in the 6 months before and after initiation of insulin therapy.
INSTIGATE is a prospective, noninterventional, multicenter study of patients with type 2 diabetes who were initiating insulin for the first time as part of their usual care in 2006. The study was conducted in France, Germany, Greece, Spain, and the UK, and observed the course of diabetes therapy for up to 6 months. Direct medical costs were evaluated from the national health care system (third-party payer) perspective at 2006 prices.
Of the 1153 patients with type 2 diabetes, 1051 (91.2%) had follow-up visits in the 6 months after insulin initiation and were included in the cost analysis. In all countries in our study, mean total direct costs per patient increased in the 6-month follow-up period, compared with the 6-month period prior to insulin initiation, and ranged from €577 in Greece to €1402 in France. The incremental cost of adding insulin treatment ranged from €81 in France to €471 in Spain.
In all countries, the mean total direct cost of care for diabetes increased after starting insulin. The breakdown of total direct costs by expenditure category varied considerably across countries, reflecting differences in resource use patterns, prices of medical resources, and different health care systems.
PMCID: PMC3531987  PMID: 23277741
type 2 diabetes mellitus; costs; resource use; insulin
21.  Clinical Outcomes After Insulin Initiation in Patients with Type 2 Diabetes: 24-Month Results from INSTIGATE 
Diabetes Therapy  2012;3(1):9.
To examine changes in insulin regimens and glycemic control during the 24 months after initiation of insulin in patients with type 2 diabetes mellitus.
Data were collected over a 24-month period from patients requiring insulin initiation as part of usual care, in a prospective, observational study. Changes in insulin regimens and hemoglobin A1c (HbA1c) were examined within countries (Germany, Greece, Spain) and overall.
Prandial insulin only was most commonly initiated in Germany, while basal or premixed formulations were initiated in Greece and Spain. In Germany, compared with Greece or Spain, the patients were slightly younger and had a shorter diabetes duration when initiating insulin. For patients overall, 76.1% did not change their insulin regimen between initiation and 24 months. The most obvious change was a shift from prandial to basal/bolus in Germany, with almost doubling of mean daily insulin dose; in Greece and Spain, more patients stopped using insulin and the trend to more complex regimens was not seen. Overall, mean (SD) HbA1c decreased from baseline (9.4 [1.7]%) to 6 months (7.2 [1.0]%), but with little further change through 24 months (7.2 [1.1]%). HbA1c change with basal/bolus insulin (−2.6 [2.0]%, baseline 10.1%) was greater than with basal only (−2.0 [1.8]%, baseline 9.3%). Mean HbA1c less than 7% was achieved and maintained over 24 months in Germany, but was not achieved at any time in Greece or Spain.
Within 24 months of insulin initiation, the majority of patients with type 2 diabetes remained on the same insulin regimen initially instigated, despite the well-established progressive loss of prandial and basal endogenous insulin secretion. Adequate glycemic control was best achieved where insulin dosage adjustments and insulin intensification took place.
PMCID: PMC3508108  PMID: 22926918
Basal/bolus insulin; Glycemic control; Insulin therapy; Insulin regimen; Prandial insulin; Type 2 diabetes
22.  An evaluation of two large scale demand side financing programs for maternal health in India: the MATIND study protocol 
BMC Public Health  2012;12:699.
High maternal mortality in India is a serious public health challenge. Demand side financing interventions have emerged as a strategy to promote access to emergency obstetric care. Two such state run programs, Janani Suraksha Yojana (JSY)and Chiranjeevi Yojana (CY), were designed and implemented to reduce financial access barriers that preclude women from obtaining emergency obstetric care. JSY, a conditional cash transfer, awards money directly to a woman who delivers in a public health facility. This will be studied in Madhya Pradesh province. CY, a voucher based program, empanels private obstetricians in Gujarat province, who are reimbursed by the government to perform deliveries of socioeconomically disadvantaged women. The programs have been in operation for the last seven years.
The study outlined in this protocol will assess and compare the influence of the two programs on various aspects of maternal health care including trends in program uptake, institutional delivery rates, maternal and neonatal outcomes, quality of care, experiences of service providers and users, and cost effectiveness. The study will collect primary data using a combination of qualitative and quantitative methods, including facility level questionnaires, observations, a population based survey, in-depth interviews, and focus group discussions. Primary data will be collected in three districts of each province. The research will take place at three levels: the state health departments, obstetric facilities in the districts and among recently delivered mothers in the community.
The protocol is a comprehensive assessment of the performance and impact of the programs and an economic analysis. It will fill existing evidence gaps in the scientific literature including access and quality to services, utilization, coverage and impact. The implementation of the protocol will also generate evidence to facilitate decision making among policy makers and program managers who currently work with or are planning similar programs in different contexts.
PMCID: PMC3488490  PMID: 22925407
India; Demand side financing; Maternal morality; Chiranjeevi yojana; Janani suraksha yojana
23.  Validity of two common asthma-specific quality of life questionnaires: Juniper mini asthma quality of life questionnaire and Sydney asthma quality of life questionnaire 
This study explored the psychometric properties (internal consistency, construct validity, discriminative ability) of the Juniper Mini Asthma Quality of Life Questionnaire (Mini AQLQ-J) and the Sydney Asthma Quality of Life Questionnaire (AQLQ-S).
One hundred fourty-six adults (18–45 years) with asthma requiring regular inhaled corticosteroids were recruited to a trial of written emotional disclosure. Correlational analyses were performed to understand the relationship of the two measures with each other, with symptoms, lung function, asthma control, asthma bother and generic quality of life. Median quality of life scores were compared according to gender, health care usage and levels of asthma severity.
AQLQ-J and AQLQ-S total scores correlated strongly with each other (rho = −0.80) and moderately with the EuroQol Current Health Status Scale (AQLQ-J: rho = 0.35; AQLQ-S: rho = −0.40). Domain score correlations between AQLQ-J and AQLQ-S were mostly moderate (0.50 < rho < 0.80).
Both QoL measures were significantly correlated with symptom score. Correlations with the symptom score asthma module (AQLQ-J: rho = −0.69; AQLQ-S: rho = 0.50) were stronger compared with the total symptom score and the symptom score rhinitis module (AQLQ-J: rho = −0.41; AQLQ-S: rho =0.31).
Neither QoL measure was significantly correlated with FEV1, % predicted at the total or the domain level.
Total scores of both measures were significantly correlated with subjective asthma control (AQLQ-J: rho = 0.68; AQLQ-S: rho = −0.61) and asthma bother (AQLQ-J: rho = −0.73; AQLQ-M: rho = 0.73).
Total AQLQ-J score and total AQLQ-S score were significantly associated with perceived asthma severity (AQLQ-J: p=0.004, AQLQ-S: p=0.002) and having visited a GP in the past four months (AQLQ-J: p=0.003, AQLQ-S: p=0.002).
This study provides further evidence for the validity of the AQLQ-J and the AQLQ-S in a British population of adult patients with asthma managed in primary care. Correlations with lung function parameters were weak or absent. Correlations with generic quality of life were moderate, those with asthma symptoms, asthma control and asthma bother were strong. Both measures are able to discriminate between levels of asthma severity and health care usage.
PMCID: PMC3478207  PMID: 22906054
24.  Polyfunctional T Cells Accumulate in Large Human Cytomegalovirus-Specific T Cell Responses 
Journal of Virology  2012;86(2):1001-1009.
Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (20 to 84 years) by using multicolor flow cytometry. CMV-specific T cells were characterized by the activation markers CD40 ligand (CD40L), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) and the memory markers CD27 and CD45RA. The proportions of effector memory T cells increased in large responses, as did the proportions of polyfunctional CD8 (IFN-γ+ IL-2+/− TNF-α+) and CD4 (CD40L+/− IFN-γ+ IL-2+ TNF-α+) T-cell subsets, while the proportion of naïve T cells decreased. The bigger the CD4 or CD8 T-cell response to pp65, the larger was the proportion of T cells with an advanced memory phenotype in the entire (including non-CMV-specific) T-cell compartment. In addition, the number of activation markers per cell correlated with the degree of T-cell receptor downregulation, suggesting increased antigen sensitivity in polyfunctional cells. In summary, our findings show that polyfunctional CMV-specific T cells were not superseded by dysfunctional cells, even in very large responses. At the same time, however, the memory subset composition of the entire T-cell compartment correlated with the size of the T-cell response to CMV pp65, confirming a strong effect of CMV infection on the immune systems of some, but not all, infected people.
PMCID: PMC3255847  PMID: 22072753
25.  Including mixed methods research in systematic reviews: Examples from qualitative syntheses in TB and malaria control 
Health policy makers now have access to a greater number and variety of systematic reviews to inform different stages in the policy making process, including reviews of qualitative research. The inclusion of mixed methods studies in systematic reviews is increasing, but these studies pose particular challenges to methods of review. This article examines the quality of the reporting of mixed methods and qualitative-only studies.
We used two completed systematic reviews to generate a sample of qualitative studies and mixed method studies in order to make an assessment of how the quality of reporting and rigor of qualitative-only studies compares with that of mixed-methods studies.
Overall, the reporting of qualitative studies in our sample was consistently better when compared with the reporting of mixed methods studies. We found that mixed methods studies are less likely to provide a description of the research conduct or qualitative data analysis procedures and less likely to be judged credible or provide rich data and thick description compared with standalone qualitative studies. Our time-related analysis shows that for both types of study, papers published since 2003 are more likely to report on the study context, describe analysis procedures, and be judged credible and provide rich data. However, the reporting of other aspects of research conduct (i.e. descriptions of the research question, the sampling strategy, and data collection methods) in mixed methods studies does not appear to have improved over time.
Mixed methods research makes an important contribution to health research in general, and could make a more substantial contribution to systematic reviews. Through our careful analysis of the quality of reporting of mixed methods and qualitative-only research, we have identified areas that deserve more attention in the conduct and reporting of mixed methods research.
PMCID: PMC3445834  PMID: 22545681

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