We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses.http://www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10%  at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123).Patients from the nilotinib registration trial  had a slow monophasic response and the remainder  had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months.Unlike newly diagnosed patients with Ph+ CML-CP—in whom the majority had a biphasic response—approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ≤ 10% at 6 months as a threshold for predicting EFS. BCR-ABL1 fusion gene. The BCR-ABL1 fusion gene is formed by a reciprocal translocation of a fragment of the Abelson gene (ABL1), situated at the breakpoint on chromosome 9, with a fragment of the breakpoint cluster region (BCR) gene on chromosome 22. This translocation forms the Philadelphia chromosome (Ph), which encodes the constitutively active BCR-ABL1 protein tyrosine kinase %) as the minimal level of detection of the PCR assay for all laboratories and treated these measurements as left-censored data. BCR-ABL1 transcript levels below 0.0032% were established as “undetectable” in the IRIS trial  ≤ 0.1%), and achieving such a response has been associated with excellent long-term outcomes ,23,34.These findings are consistent with other studies showing that early molecular responses were associated with superior EFS and overall survival ,35-37. TWe note that it may seem counterintuitive to use this model to categorize a patient as a fast biphasic responder when only 3 to 6 months of data is available, and the β phase is not yet observable. In using the biphasic model even in the presence of limited information, we are making use of prior information from both IRIS as well as this study, where almost all fast responders ultimately have a β phase. Furthermore, in some cases, the β phase does occur before month 6 Figure D, so accR″(t)), or the point where Aeαt = Beβt. We found that the point of maximum curvature definition most consistently agreed with our estimation of where the transition point should lie based on clinical experience.Because the definition of the transition point as the point of maximum curvature was somewhat complex, we initially tested simpler definitions for the transition point, such as the point of maximum second derivative  above or below 10% at 6 months. Furthermore, the NPV of all the classifiers in the model was relatively low (maximum of 62%). This may be due in part to 2 years of follow-up being too short and that, over longer times, the monophasic patients may continue to be more likely to progress than the biphasic patients. The NPVs and PPVs depend on the prevalence of second-line patients who do not respond well to nilotinib therapy; this prevalence may be lower in a controlled trial than in the general population. Nevertheless, PPV and NPV are preliminary tools for comparing the predictive power of different methodologies. Our modeling approach represents one of many classification schemes that can be used for dividing a population into two groups. In the future, we could consider exploring other classification approaches, such as neural networks or support vector machines.Key benefits of the modeling approach (classification of a second-line patient as either a fast or slow responder) are that (1) the model helps to identify 6 months as an ideal follow-up time; and (2) the model provides a natural means for incorporating all measurements and treating the BCR-ABL1 dynamics as a continuous variable up to the time at which classification takes place. In the clinic, samples may be missed or multiple conflicting measurements may be obtained in the same time period. In these instances, a simple algorithm may not be able to adequately determine patient response based on one data point at a particular time. The model, however, provides a natural technique for integrating missing data and multiple samples at the same time, and produces a dichotomous classification associated with EFS. While we required patients to have at least three data points in the first 6 months, the NLME approach used here can work with fewer data points such that a patient with only one assessment at month 6 could be classified as a fast responder if he or she has achieved BCR-ABL1 (IS) ≤ 0.1% (at least MMR) or a slow responder if his or her BCR-ABL1 levels are above 10%. In the future, it will be useful to investigate how the model performance changes depending on the amount of data collected.A related modeling approach that also treated BCR-ABL1 response as a continuous parameter was recently reported . In thisThe nilotinib registration trial demonstrated high rates of major cytogenetic response (59%) and complete cytogenetic response  . Most paThis work represents an exploratory step in using a model to measure response based on BCR-ABL1 as a continuous variable and transform it into a dichotomous classification associated with EFS. Because the patient subpopulation in this study was highly heterogeneous and the subpopulation used to compare different predictors was small (n = 76), more testing and validation will be necessary before this approach can be directly applied in the clinical setting.Landmark analyses, in which longer-term outcomes are analyzed according to achievement of molecular milestones at early time points (3 and 6 months), have become an increasingly common means of evaluating responses to both front- and second-line TKI therapies used for the treatment of CML. However, this emphasis on achieving specific molecular targets may be challenging in routine clinical practice, where samples are frequently missing. Here, we described a mathematical model that utilizes the full BCR-ABL1 transcript profile to predict longer-term responses among patients treated with nilotinib after imatinib failure. Evaluating BCR-ABL1 transcript dynamics over time in an individual patient may provide a more robust and practical method for classifying patient response.CML: Chronic myeloid leukemia; ABL1: Abelson gene; BCR: Breakpoint cluster region; Ph: Philadelphia chromosome; IRIS: International Randomized Study of Interferon and STI571; CP: Chronic phase; AP: Accelerated phase; RQ-PCR: Real-time quantitative polymerase chain reaction; IS: International scale; EFS: Event-free survival; MMR: Major molecular response; NLME: Nonlinear mixed effects; MR4.5: Molecular remission at 4.5 logs; PPV: Positive predictive value; NPV: Negative predictive value; IC50: Half maximal inhibitory concentration; CCyR: Complete cytogenetic response.Dr Stein is an employee of Novartis. Dr Martinelli acted as a consultant for Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Genzyme, and received honoraria from Novartis and Bristol-Myers Squibb. Dr Hughes acted as a consultant for and received honoraria and research funding from Novartis and Bristol-Myers Squibb. Dr Müller acted as a consultant for and received honoraria from Novartis and Bristol-Myers Squibb and received research funding from Novartis. Dr Beppu and Dr Gottardi have nothing to disclose. Dr Branford acted as a consultant for and received research funding from Novartis and received honoraria from Novartis and Bristol-Myers Squibb. Dr Soverini acted as a consultant for and received honoraria from Novartis, Bristol-Myers Squibb, and ARIAD Pharmaceuticals, Inc. Dr Woodman is an employee and shareholder of Novartis. Dr Hochhaus acted as a consultant for and received honoraria and research funding from Novartis, Bristol-Myers Squibb, Pfizer Inc., and ARIAD Pharmaceuticals, Inc. Dr Kim acted as a consultant for and received honoraria from Novartis and Bristol-Myers Squibb. Dr Saglio acted as a consultant for and received honoraria from Novartis and Bristol-Myers Squibb. Dr Radich acted as a consultant for Novartis, Bristol-Myers Squibb, Pfizer Inc., and ARIAD Pharmaceuticals, Inc., and received research funding from Novartis.AMS, AH, JPR, RCW, and TPH participated in the design of the study and analyzed and interpreted data. D-WK, EG, GM, GS, LB, MCM, SB, and SS collected, analyzed, and interpreted data. All authors drafted, read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/173/prepub


Funding statement should read "This study was supported by Program from the National Basic Research Program (973) of China (2012CB518804), the National Natural Science Foundation of China (31172319), the key Technology R?D Program of Jiangsu (BE2009388), the Fundamental Research Funds for the Central Universities (KYT 201003), and the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."


Community-based care (CBC) can increase access to key services for people affected by HIV/AIDS through the mobilization of community interests and resources and their integration with formal health structures. Yet, the lack of a systematic framework for analysis of CBC focused on HIV/AIDS impedes our ability to understand and study CBC programs. We sought to develop taxonomy of CBC programs focused on HIV/AIDS in resource-limited settings in an effort to understand their key characteristics, uncover any gaps in programming, and highlight the potential roles they play. Our review aimed to systematically identify key CBC programs focused on HIV/AIDS in resource-limited settings. We used both bibliographic database searches  for peer-reviewed literature and internet-based searches for gray literature. Our search terms were ‘HIV’ or ‘AIDS’ and ‘community-based care’ or ‘CBC’. Two co-authors developed a descriptive taxonomy through an iterative, inductive process using the retrieved program information. We identified 21 CBC programs useful for developing taxonomy. Extensive variation was observed within each of the nine categories identified: region, vision, characteristics of target populations, program scope, program operations, funding models, human resources, sustainability, and monitoring and evaluation strategies. While additional research may still be needed to identify the conditions that lead to overall program success, our findings can help to inform our understanding of the various aspects of CBC programs and inform potential logic models for CBC programming in the context of HIV/AIDS in resource-limited settings. Importantly, the findings of the present study can be used to develop sustainable HIV/AIDS-service delivery programs in regions with health resource shortages. The Joint United Nations Program on HIV/AIDS (UNAIDS) estimated that globally approximately 34.2 million people were living with HIV in 2011 , access The chronic shortage of health workers amplifies this challenge. According to the Global Health Workforce Alliance, 1.5 million more health care workers are needed in sub-Saharan Africa alone just to be able to provide basic health services . FurtherThere is currently no single consensus definition of community-based care (CBC) . It can The use of community health workers (CHWs) was integrated into primary healthcare reform in the 1970s , 22. As With the scale-up of ART in the global South came new challenges: delivering treatment to those in need and providing lifelong care for those now on life-extending treatment –27. To mWith ART coverage increasing in many settings, understanding the role of CBC programs becomes more and more important . RelatedWe conducted electronic searches of health bibliographic databases including PubMed via Medline (from inception to December 2011), CINAHL (from inception to December 2011), and EMBASE (from inception to December 2011). Our search terms were ‘HIV’ or ‘AIDS’ and ‘community-based care’ or ‘CBC’. Additional articles were sought by examining the bibliographies of relevant articles. For the gray literature, we used the same search terms in Google and Google Scholar to identify program descriptions, study reports, and publications of official materials issued by non-governmental organizations, government health services, and international agencies. Site-specific searches of the UNAIDS and WHO websites were also undertaken.In the present study, only CBC programs operating in resource-limited country settings were included. We defined resource-limited as a low-income or middle-income country using the World Bank Country Classification . As we bFor analysis, we undertook an inductive and iterative process to develop our taxonomy of CBC programs. First, Beth Rachlis (BR) conducted the search of potentially relevant CBC programs (as case studies) and determined which programs provided data based on our inclusion criteria. Next, BR extracted all descriptions from each included CBC program. From the gathered information and using an inductive approach, BR and Sumeet Sodhi (SS) sorted the data and descriptions extracted from each individual program into broader categories, in an iterative process. Finally, we sought to organize the information into distinct and mutually exclusive categories (e.g. program scope vs. program operations). For content validation, we ensured that the information described and extracted from most individual programs could be categorized as per our developed taxonomy.n=45), were not based in a resource-limited setting (n=10), or were duplicates (n=9). We updated our literature search in February 2012 and found two additional programs that were relevant. Therefore, 21 CBC programs  of ‘a world without AIDS’ or Dignitas’ pledge ‘to stand up for those who lack access’. Most included programs provided a mission statement to describe what they seek to accomplish. Examples include the Centre for Positive Care ‘to reduce the spread of Sexually Transmitted Infections (STIs), HIV/AIDS, and to improve the quality of life’; SERVANTS to ‘improve the lives of the poor’; or Men as Partners to ‘mobilize men to become actively involved in countering HIV and gender-based violence’.Urban–rural location can influence program delivery options and resources. The majority of CBC programs in this study described working with urban populations  although semi-rural (e.g. Tumelong Hospice) and rural (e.g. Chirumhanzu HBC) settings were also represented. A few included programs serve both rural and more urban populations (e.g. FACT). While CBC programs focused on HIV seek to work with PLWHA, many programs also cater to others affected by HIV – family members (e.g. Centre for Positive Care) and orphans and vulnerable children (OVCs) . Less common were programs that work with high-risk populations such as prisoners or migrants . Pathfinder International specifically described targeting marginalized populations, including drug users, sex workers, and displaced persons.Two broad categories were judged relevant here – location and types of services provided. In terms of location, some programs only describe operating directly inside the private homes of their clients through home-based care (e.g. Moretele Sunrise Hospice HBC) while others report operating in more shared community settings . Most commonly, programs provide care both inside and outside of the home, with some aiming for multiple locations, including a clinic or hospital (e.g. Lusikisiki Clinic).CBC programs differed most on the range of services provided as we noted heterogeneity regarding types of services provided over different time points along the continuum of care. Common services reported include HIV prevention, including risk reduction activities ; HIV Testing and Counseling (HTC) (e.g. HIV Equity Initiative); Prevention of Mother-to-Child Transmission (PMTCT) (e.g. Centre for Positive Care); ART provision and follow-up, including adherence monitoring ; medical and nursing support, including treatment of STIs and management of symptoms and opportunistic infections ; nutrition support and food supplementation (e.g. FACT); palliative care (e.g. Tumelong Hospice and Lekegema Orphan Haven); financial support in the form of income-generating activities (IGA) or community funds (e.g. Khutsong Centre and Heartbeat Orphan Programme); material support, including technical support; information, communication, and education activities ; and psychosocial support (e.g. Catholic Diocese in Ndola). Such heterogeneity is at the core of challenges involved in evaluating outcomes of such programs.A number of important characteristics relate to the manner in which programs situate themselves in relation to community structures. First, we found that programs can be classified by the extent of community engagement and/or participation. In some CBC programs, community leaders or volunteers are included in overall operations management (e.g. Catholic Diocese in Ndola). Almost all programs where detail was provided implied the need to maintain and incorporate community life. For example, by seeking to build on traditions of family support, Chirumhanzu HBC project encourages a mutual obligation in the way they run their programs and deliver their services. Programs like FACT and Reach Out Mbuya incorporate church life, and in programs like the Thandanani Children's Foundation, it is the community leaders and the residents that primarily identify at risk individuals in need of their services. The number of partners and collaborators not only affects program operations but also may reflect a program's ability to build capacity in the broader community. In terms of program reach, not all included CBC program descriptions had available data, but among those that did, most have at least sub-district (e.g. Luskikiki clinic) or district-level reach . Programs like TASO, STEPS, and Moretele Sunrise Hospice HBC serve patients in more than one district and can be considered multisite. To achieve coverage, programs decentralize  or, through advocacy, they mobilize communities (e.g. Thandanani Children's Foundation). Finally, the extent to which CBC programs are embedded within formal health and social structures varies. Most programs reported linkages and collaborations with local organizations and government structures/ministries . However, some of the programs described operate independently (e.g. HIV Equity Initiative/Zamni-Lasanti).Financial aspects of the program are crucial – identifying who funds the program and how the funds are disbursed. Sources of funds described ranged widely between programs, with common sources including a combination of local and foreign governments , private donors , national or international NGOs , and individuals and businesses within the community . Program costs and budgets were generally not provided in the sources examined. A few programs, such as Pathfinder International, did make their annual financial reports that documented expenses publicly available.The organizational structure and staff composition of the CBC programs varied considerably, particularly with respect to the type of CHWs involved . The exact hierarchical structure was described only in a few programs , although most provided information on the presence of a board of directors , advisory boards , or other governance groups (e.g. HIV Equity Initiative). Some programs only described recruiting volunteers (e.g. SERVANTS) although more common were programs where a combination of paid staff and volunteers were recruited . The methods, frequency, and level of training also ranged across included programs, as did the extent of volunteer and staff supervision or mentoring. When described, common strategies included on-the-job or ongoing training (e.g. Moretele Sunrise Hospice) or the provision of training sessions on specific topics . Among programs where information was available, management and supervision levels also varied although included programs commonly described incorporating a coordinator to supervise volunteers . Foreign doctors or senior nurses also provide supervision in programs such as Dignitas International, Lusikisiki Clinic, and HIV Equity Initiative. Some programs describe peer-based activities, including Pathfinder International and TASO's ‘training of the trainers’ program.According to our taxonomy, key factors influencing the sustainability of CBC programs include the availability of ongoing funding, the ability of the program to adapt to local contexts and to replicate itself in new settings, and high staff retention levels. According to the included programs, strategies used to retain staff include providing volunteers with a stipend or other incentives such as recreational activities and family support . Also, important for sustainability of programs is their ability to adapt to any changing local contexts and situations and, where appropriate, their replicability in new settings. We found few programs describing such replication; examples include STEPS and the HIV Equity Initiative. Dissemination, capacity building, and knowledge translation activities were described in several programs .Finally, the frequency and comprehensiveness of monitoring and evaluation activities varied. Programs such as the Catholic Diocese in Ndola described conducting biannual evaluations although specific details regarding these evaluations were generally not provided. Some programs provided quality indicators  or potential program impacts  and have a specific team for evaluation and monitoring activities . Inputs, such as management structures and financial accountability (e.g. STEPS), and outcomes, such as changes in behaviors  and clinical outcomes (e.g. Lusikisiki Clinic), were also described with respect to monitoring and evaluation activities.The taxonomy presented here elaborates nine key categories useful for describing and organizing CBC programs focused on HIV/AIDS in resource-limited settings. Our findings can help to identify what is currently being done with respect to addressing the needs of PLWHA, highlighting any potential gaps in programming.The majority of CBC programs included in our review described programs operating in sub-Saharan Africa, which is consistent with previous literature , 48.Visions and program missions varied, although generally identified CBC programs strive to improve the lives of those living with HIV/AIDS. The specificity of the program's mission not only impacts upon the types of services offered but can also affect a program's ability to expand and adapt into new settings. While the vast majority of included programs targeted PLWHA, many also incorporated other affected populations, including family members and OVCs. A few CBC programs included vulnerable populations, such as drug users and migrant workers. Marginalized populations remain a priority population for HIV care, treatment, and support although they are generally underserved . Few proThe types of services offered varied considerably among the CBC programs studied, although most described providing services both in the home and in more public community settings. Interestingly, in a review of South African CBC models, four common program types emerged: 1) funding, technical assistance, and support; 2) counseling, education, and an IGA component; 3) the two aforementioned points plus home visits; and finally, 4) comprehensive programs which add to item 3) above, additional levels of nursing care . Adding Operational models also differed across programs included in the present review. In particular, the level of community engagement appeared to vary, as evidenced by the number and nature of collaborations and partnerships with community groups, members, and leaders. Importantly, the ability to build and maintain collaborations with community partners is essential to ongoing program operations. Related is how CBC programs are embedded within existing formal structures which include: the identification of community partners for potential collaboration, a sense of ownership by the community, their relevance to local needs, integration into existing systems, and periodic reviews and program updates with new knowledge . The avaFunding models, human resources factors, and the sustainability of CBC programs have also been included as part of our taxonomy and are all essential elements of program impacts. Interestingly, a recent review noted that factors influencing HBC program effectiveness include those that relate to human resources, funding mechanisms, and an ability to adapt to local contexts . FurtherWhile most programs make reference to some type of regular monitoring, many programs provided limited information regarding their monitoring and evaluation strategies or the information that was collected during their evaluations. However, CBOs are playing greater roles in both the design and implementation of research in order to effectively inform program and policy decisions , 61. ThiSeveral limitations must be considered when interpreting this review. First, the comprehensiveness of our review is limited because many CBC programs do not publish or make vital information publicly available. As our search strategy relied heavily on electronic resources, our review contains only those programs with access and capacity to publish their program details online. Even when data were available, not all CBC programs were included as we sought to represent typical, known programs. This may affect the generalizability of our taxonomy. More specifically, programs that solely target marginalized groups, including men who have sex with men, sex trade workers, and/or migrant populations, were underrepresented in our review. However, we did attempt to include a range of programs which, in addition to targeting the general population of PLWHA, targeted marginalized groups as well . Furthermore, CBC programs originated from several regions, though not all. Nevertheless, the present study helps to disentangle general versus country-specific characteristics of CBC programs , 63. FinHuge sums of money are now being invested into multi-sectoral approaches and there have been extensive efforts to assess the effectiveness of traditional public health interventions in terms of prevalence rates and numbers of infections averted . CurrentIn brief, through a clear vision, a need for a program is identified. This overall vision or mission helps to motivate and guide program development, including the specification of a target population and program scope. The inputs to the program include available funding and human resources. These inputs are needed to provide the target population a certain set services (program scope) using a specific approach (program operations). These can be considered our outputs. The number of households captured or the number of eligible patients initiated on ART offer some examples of outputs that could be described. The overall program outcomes would be effectiveness, the degree to which the program is meeting its goals , and susArguably, continuous feedback and quality improvement through regular monitoring and evaluation can facilitate any recommended rapid changes in the program to improve functioning and effectiveness . EvaluatImportant considerations include whether programs have identified resources for monitoring and evaluation activities. Improved methods for data collection, clearly defined indicators of success, and well-maintained ongoing monitoring and evaluation systems are crucial for program planning and effective implementation , 66, 67.High costs and a lack of adequate health infrastructure can challenge the scale-up and uptake of HIV-related services in resource-limited settings. Chronic health worker shortages have resulted in the decentralization of HIV care and a movement toward the use of non-physician-based models of care , 28, 70.Our taxonomy, focused on HIV/AIDS in resource-limited settings, classifies CBC programs by nine key areas: region, vision, target populations served, program scope, program operations, funding models, human resources, sustainability, and monitoring and evaluation strategies. While further study is needed, our findings can provide insight on current CBC models as well as potential gaps in programming. Furthermore, the presented taxonomy can inform potential logic models that can be used to enhance overall program performance. In the context of ART scale up, our findings have potential for use in the development of evidence-based tools for sustainable HIV/AIDS-service delivery in regions currently facing, or at risk for, severe health resource shortages.


Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) prevalence have been reported in populations that do not regularly access health centres for sexually transmissible infections (STI) testing. We reviewed current outreach strategies used to increase access to STI testing and their outcomes.High We systematically reviewed the literature for English language studies published between 1 January 2005 and 28 January 2011 describing CT and/or NG screening programs in non-clinical outreach settings.We identified 25 programs, with the majority occurring in either Australia (32%) or the United States (32%). The most common target groups were young people aged 15–29 years (52%), men who have sex with men (24%) and sex workers (8%). The median CT positivity was 7.7% , and median NG positivity was 2.6% . The median participation rate was 53% (IQR: 23.9%-81.3%), and a median of 79.6% (IQR: 55.1%-89.4%) of participants were tested, with a median of 100 tests conducted per program . Across all settings the participation rate was highest among target groups gathering in community service venues  , and social venues (sporting venues or bars) . Lower participation rates were found in street/public community areas  and sex on premises venues .The review indicated that although CT and NG outreach programs reached a relatively small number of people the yield of infections is high. Settings which appear to be more effective at encouraging participation appear to be those within an existing venue, rather than in public areas. Chlamydia trachomatis (CT) is the most commonly reported notifiable infectious disease in the United States, Australia and many European countries with notifications increasing steadily each year . Disagreements were resolved through discussion and consensus obtained. A paper was included if it described an outreach program which was: led by an external organisation and offered CT and/or NG screening in person to populations in the community, street or at a specific venue ; the screening activity was primarily focused on increasing access to STI testing among populations at risk for STIs; and the study reported at least the number of STI tests conducted. Studies were excluded for the following reasons: the outreach program was undertaken in an institution where daily attendance was compulsory such as a school, workplace or detention centre; the testing occurred in a clinical setting where STI testing routinely took place; postal screening kits were mainly used; screening was conducted within a cohort study or a randomised controlled trial; the study was designed to estimate STI prevalence; anonymous testing was conducted with results and treatment withheld from participants; specimens were not self-collected; and no original data were presented e.g. review, editorial.For the studies which met the inclusion criteria, information was extracted on the target group, setting, infections tested for, recruitment details, incentive use, specimen collection method, type of specimens collected, test results and case and partner notification method. Quantitative data were also extracted on the number of people invited who agreed to participate, the number of participants tested, the number of positive CT and NG tests, the number of individuals notified of their results and treated after a positive test, the number sexual partners which were notified of possible contact with a STI and treated, and any information on costs.The following definitions were used throughout the review:i. Participants: people who were approached and agreed to participate in the screening activityii. Participation rate: the number of participants divided by the number of people approachediii. Testing rate: the number of specimens collected divided by the number of participantsiv. Positivity: the percentage of tests which were positivev. Results notification rate: the percentage of people with a positive test who were informed of their resultsvi. Treatment rate: the proportion of people with positive result who were treated.We conducted a frequency analysis of the outcomes extracted. For the participation rate, testing rate and positivity outcomes we calculated the median and inter-quartile range (IQR) across programs. We described the overall outcomes for all programs included in the review, then focused primarily on the participation and testing rates for each different setting type and population group, including; young people (age 15–29 years), MSM, sex workers based outside of registered brothels, travellers in hostels, men living in temporary settlements in South Africa, clients of homeless shelters, and attendees of community centres. Setting types were grouped as; (i) community or street based and (ii) venue based outreach. Venue based outreach was then further divided into; (i) sex venues, (ii) community services venues and (iii) social venues (including bars and sporting venues).The initial search identified 3219 unique articles for which the titles and abstracts were reviewed; 3201 were excluded leaving 18 papers in the review  followed by MSM (24%) then female sex workers (8%). Other groups included: attendees of community centres, travellers staying in hostels, clients of homeless shelters and settlement dwellers in South Africa (Table The majority of programs offered screening for CT only (40%), CT / NG only (32%), and HIV and/or syphilis in addition to CT / NG (28%). Of the 25 programs the median number of tests conducted was 100 . Participation rates were documented in ten programs, with a median of 53% . Testing rates were documented in 14 programs, with a median of 79.6% . Nineteen programs reported CT positivity with a median of 7.7% (IQR: 3.0% - 11.1%). The median NG positivity in ten programs was 2.6% (IQR: 0.0% - 8.0%).Of the 25 programs, nine (36%) described using incentives to encourage participation , ten programs did not specify incentive use and a further six programs did not use incentives. Seven programs documented the result notification rate, with a median of 100% (IQR: 81% - 100%). These programs used a combination of in-person, phone, SMS, mail and email to provide participants with their results. Treatment rates were documented in eight programs, the majority (75%) of these documented treatment rates of 100%. No programs documented partner notification outcomes.Program costs were available in four programs. Morris et al. calculated costs per CT test taken and cases detected in two Californian youth programs in street settings and parenting centres. Costs were calculated by dividing hours worked by number of tests taken and the number of positive CT tests. Street settings took 2.3 person hours per test and 43 hours per case detected. Parenting centres took 0.9 person hours per test and 13.5 hours per case detected. To increase participation peer volunteers were used in a number of screening sites, however volunteer hours worked were not included in the overall cost calculations . Buhrer-Of the 13 youth outreach programs the majority were conducted in Australia (38%) and the United States (US) (38%) Table . Common The highest participation rate (81.7%) (tests=74) was reported by Gotz et al. involving outreach among new immigrants, school dropouts and people from vocational schools who met regularly at a community service venue in the Netherlands . A high Johnson et al. also reported a high participation rate (79.6%) (tests=1808) in a program in the US family court system where collection of a urine sample was mandatory for drug testing. Young people were asked to consent to a small portion of this urine sample being tested for STIs .The lowest youth participation rate was in a program targeting youth at a festival (21.3%) (tests=68) where health staff held a stall offering STI testing . MarrazzThe highest testing rate (85.2%) (tests=92) was found by Gold et al. in a program in Australia where football clubs agreed to have screening offered in club rooms after training . High teThe six programs targeting MSM were conducted in Australia, the US, Canada and the United Kingdom (UK), mainly within sex on premises venues 83%) -33  and 24.3% (tests=521). The authors compared two systems of outreach in the same venues over consecutive years to describe if a comprehensive program compared to an anonymous program increased clients receiving results and treatment. The anonymous program did not collect any identifying information from participants, instead participants were given a card with a unique study identifier and a phone number to call for their results . The comTesting rates were documented in five programs. Emerson et al. reported the highest testing rate (96.5%) (tests=167) in a program which targeted MSM at two sex on premises venues in the UK and involved offering testing monthly . Lister Two outreach programs, both reported by Wi et al. targeted sex workers. The programs were designed to increase access to preventative health care for street based sex workers and guest relations officers in karaoke bars in the Philippines . TestingLewis et al. described an outreach program targeted at men living in temporary settlements in South Africa. The program was requested by the local male residents and involved a mobile van offering STI and HIV screening fortnightly, with participants completing a brief demographic and behavioural questionnaire prior to testing. A total of 301 men were tested, the participation rate was not reported, however the testing rate was 97.4%. The CT positivity was 8.6% and NG positivity was 6.3% .The highest participation (96.7%) and testing rates (98.6%) (tests=410) in the review were found in an outreach program targeting clients of homeless shelters. The CT positivity was 10.8% and NG positivity was 4.1%. Nearly all participants (98%) were informed of their results and 91% of those testing positive were treated. Study staff provided treatment at the homeless shelter, and participants unable to be located for treatment were referred to the health department for follow-up . ParticiBuhrer-Skinner et al. offered screening to travellers staying in budget hostels. Outreach staff provided an education session in the evening then offered STI testing at the completion of the session. Of the 65 tests conducted the CT positivity was 7.7%. Participation and testing rates were not documented.Rusch et al. offered STI screening to a group of women and transgender people  attending a community venue. STI screening occurred during a weekly program which provided food and general health care. Participants were offered $10 for participating and completing a questionnaire describing demographics, drug use, sexual activity and health care access. Participation rates were not recorded, however the program reported a testing rate of 73% (tests=92), the CT positivity was 2.2% and no NG cases were detected .This review indicates that since 2005 outreach programs for CT and NG have been conducted in a range of populations across a wide variety of settings. Although the programs reached a relatively small number of people, the yield of infections was high. Settings which appear to be more successful at encouraging participation were those where screening was offered within an existing venue  or sporting club, rather than on the street or public community areas.The strength of this review is that we included programs from a variety of countries and population subgroups to increase the generalisability of the findings. This review also has some limitations. First, we did not search the grey literature so it is possible that other unpublished outreach programs were not identified. Second, we restricted the search to 2005 to focus on the current outreach methods using NAAT. Third, due to the heterogeneity of the programs and outcomes we were unable to conduct a meta-analysis. Fourth, many of the programs did not provide the necessary data to calculate participation or testing rates. Fifth, search criteria did not include any cost studies reported which related to the programs included in this review. Finally, it is difficult to disentangle the elements of the programs which may have resulted in high participation rates.The highest participation rates appeared to be in venues providing a community service, and social venues such as sporting clubs and bars, whereas the lowest participation rates were in the street or public community areas and male sex venues. The relatively higher participating rate in community service venues or sporting clubs may be due to a number of factors. Recruitment in venues would be supported by the venue managers, and thus potential participants may feel more comfortable participating where trusted and known venue staff may be more active in assisting with recruitment. Second, as the venue is a closed environment participants would see others participate which would reassure them about their own involvement.It is possible that the approach, type of staff, use of peers and incentives used in programs may also influence the participation rate however there were limited information in many studies to explore this formally. A third of programs included in this review specified the use of peers in their outreach, with Morris et al. showing the use of peer volunteers increased chlamydia case detection by 3.2% (CI 1.3 – 7.8) compared to outreach where peer volunteers were not used . IncentiOutreach programs require significant effort and labour to implement . Our revIn addition to the testing uptake by the target group, the success of screening depends on treatment rate. Seven programs documented the rate of notification of results with a median of 100% being notified. Outreach programs included in this review used a combination of methods  to give participants their results, innovative methods are often required as the initial physical contact may be the only one the service has with the participant. This contrasts with clinical and educational settings, where there is greater opportunity to provide results as the client may be a regular patient of the clinic or in the case of students they attend schools daily, and there is often a school clinic which they can attend at times convenient to them, and thus can be followed up relatively easily .To maximise the benefits of outreach, programs should specifically target groups at risk of STIs who have limited access to sexual health services. The key aim of an outreach initiative should be to respond to an unmet need, rather than simply trying to maximise testing numbers. Most programs in the review targeted such populations, however only 60% of the programs actually recorded the health seeking behaviour of the target groups.Outreach STI testing programs were established in a range of settings and many targeted populations with a high yield of infections. Therefore in populations and areas where access to sexual health services is limited, supplementing existing clinical services with strategies such as outreach programs is worth considering. The review provides some insight into strategies which can maximise the participation and testing rates and yield of infections in outreach programs, and also methods for providing treatment outside of clinical settings.The authors declared that they have no competing interests.BH undertook the analysis of results obtained through the systematic review and drafted the manuscript, MJ undertook the systematic review, JM and LM edited the manuscript, JK edited the manuscript and provided advice with the design of the analysis, RG provided overall guidance with the analysis design and assistance in drafting the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/1040/prepub


Administration of cocaine increases locomotor activity by enhancing dopamine transmission. To explore the peripheral mechanisms underlying acupuncture treatment for drug addiction, we developed a novel mechanical acupuncture instrument (MAI) for objective mechanical stimulation. The aim of this study was to evaluate whether acupuncture inhibition of cocaine-induced locomotor activity is mediated through specific peripheral nerves, the afferents from superficial or deep tissues, or specific groups of nerve fibers. Mechanical stimulation of acupuncture point HT7 with MAI suppressed cocaine-induced locomotor activity in a stimulus time-dependent manner, which was blocked by severing the ulnar nerve or by local anesthesia. Suppression of cocaine-induced locomotor activity was elicited after HT7 stimulation at frequencies of either 50 (for Meissner corpuscles) or 200 (for Pacinian corpuscles) Hz and was not affected by block of C/Aδ-fibers in the ulnar nerve with resiniferatoxin, nor generated by direct stimulation of C/Aδ-fiber afferents with capsaicin. These findings suggest that HT7 inhibition of cocaine-induced locomotor activity is mediated by A-fiber activation of ulnar nerve that originates in superficial and deep tissue.  Shenmen (HT7), located at the ulnar side of the wrist, suppresses drug self-administration behavior or relapse to abused drugs such as cocaine, morphine and ethanol [Acupuncture is widely practiced for treating many functional disorders such as substance abuse, pain and psychological problems, although there are still many unresolved issues related to its effectiveness. In 1997, the NIH released a consensus statement concluding that acupuncture is effective or at least useful for the treatment of 13 conditions including drug addiction, low back pain and stroke rehabilitation [ ethanol -5. The c ethanol  and supp ethanol ,4. We ha ethanol ,5,6. Alt ethanol , and acu ethanol . The preMale Sprague-Dawley rats  were used. All rats had free access to food and water and maintained on a 12 hr light-dark cycle. All procedures were approved by the Institutional Animal Care and Use Committee at Daegu Haany University (DHU2012-008). Each group consisted of 6–8 rats, unless stated otherwise. Resiniferatoxin , an ultrapotent capsaicin analogue known to block afferents containing transient receptor potential vanilloid receptor (mostly C- and Aδ-fibers) , was disA novel mechanical acupuncture instrument (MAI) was developed to mimic the vibrations produced by manual acupuncture stimulation. This device consisted of a custom-made control unit and a cell phone vibrator  mated to an acupuncture needle . To contTo measure intensity and frequency of mechanical stimulation (vibration) by MAI, a tip acupuncture needle was attached to an accelerometer  which converted acceleration or frequency from motion to voltage. The signals from the accelerometer were digitized using a data acquisition card  and sent to a customized LabVIEW  virtual instrument software program for analysis of intensity (acceleration) and frequency of vibration. Locomotor activity was measured by an image analysis system . In a dimly-lit room, each animal was placed in a square open field box (40 cm × 40 cm× 45cm) made of black acrylic. Animal activity was monitored with a video camera mounted above the box. Video tracking software (Ethovision 3.1) measured the distance travelled (cm) by the animal. On the testing day, animals were habituated for 60 min in the open field. After recording baseline activity for 30 min, the animal was given an intraperitoneal injection of cocaine (15 mg/kg) and monitored for up to 60 min after injection. The distance travelled during each 10-min period was analyzed. Data were expressed as a percentage of baseline or total travelled distance (cm) for 1 hour. To identify the peripheral nerves mediating the acupuncture effects of HT7, major peripheral nerves innervating the forearm were selectively cut near the elbow, as described in detail ,15. RatsTo determine which afferent fibers, large A- or C/Aδ- fibers, mediate the acupuncture effects of HT7, a specific C/Aδ-fiber blocker resiniferatoxin (RTX) was administered perineurally in the ulnar nerve of both forelimbs, as described previously . In brieAnother set of experiments was carried out to confirm blockade of C-fiber transmission by RTX, by using an IB4 tracing method . In brieTo characterize the types of afferent fibers innervating HT7 acupoints, a retrograde tracer DiI was injected into the muscle  below thTo test if the DiI-positive DRGs were activated by HT7 MAI stimulation, we assessed the expression of neuronal activation marker c-Fos in the DiI-positive DRGs in two rats. Two weeks after DiI injection into HT7, MAI stimulation for 60 sec was applied to left HT7 and the right HT7 was untreated to compare as control. Twenty min later, the animals were perfused and DRGs of C8 and T1  were taken out for c-Fos immunohistochemistry. Sections of DRGs on gelatin-coated slides were incubated with c-Fos  followed by Alexa Fluor 488 goat anti-rabbit . Each tissue section was imaged under an Olympus AX70 fluorescence microscope . The number of c-Fos labeled neurons was compared between left (HT7-MAI stimulation) and right  DRGs. Data for c-Fos are expressed as a percentage of c-Fos expressing cells per DiI positive neurons. To verify which types of fibers were activated by MAI stimulation of HT7, single-unit recordings were performed as described previously ,18,19. TData are presented as mean ± SEM (standard error of the mean) and analyzed by one- or two-way repeated-measurement analysis of variance (ANOVA), followed by post hoc testing using the Holm-Sidak method or paired Student’s t-test, where appropriate. P≤ 0.05 was considered statistically significant. 2). Vibration frequencies ranging from 70 ~ 90 Hz were detected in the tip of acupuncture needle upon manipulation (data not shown). However, considerable variations in intensity and frequency were observed within each operator or across operators. Based on these findings with operators, the mechanical acupuncture instrument was preset at 1.3 m/sec2 in intensity and 85 Hz in frequency for subsequent experiments , maintained up to 1 min after insertion of the needles and then withdrawn. In 0-, 10- and 20-sec groups, the increase of cocaine locomotion was significantly inhibited in a stimulus time-dependent manner  and 2 well-trained operators with experience over 2 years in acupuncture experiments #3, #4; . After b2 and 1.3 m/sec2 groups. As the intensity (magnitude) of vibration is proportional to the acceleration [2) by varying the input voltage (1.5 -3 V) (2) were applied for 20 sec to the needles inserted at a depth of 3 mm into HT7. Control rats received only cocaine injection without acupuncture treatment. Compared to controls, both intensities significantly attenuated the locomotor response to cocaine . There was no significant difference between 0.9 m/sec2 and 1.3 m/sec2 groups  was applied to LI5, on the opposite side of HT7 on the wrist. MAI LI5 stimulation did not show any significant effect on cocaine locomotion  . One min2 groups , suggestcomotion , indicatTo identify the role of peripheral nociceptors in the HT7 MAI stimulation, we evaluated the effects of local anesthetic application at acupoints prior to needle stimulation. Rats were randomly assigned to 3 treatment groups: (1) Con, cocaine only; (2) Bupivacaine + HT7. Bupivacaine (30 ul) was injected into HT7 30 min before cocaine and acupuncture; and (3) Saline+HT7, saline instead of bupivacaine was injected. Thirty minutes after bupivacaine injection, the rats were given cocaine (15 mg/kg) followed by a 20-sec mechanical stimulation of the HT7 point. Local injection of bupivacaine at HT7 acupoints tended to inhibit acupuncture effects, compared to saline-treated controls , suggesting that peripheral nerve afferents mediated the acupuncture effects . To determine the origin of afferent fibers mediating the acupuncture effects, whether they were cutaneous or deep tissue afferents, the acupuncture needle was inserted into HT7 at a depth of either 1 mm or 3 mm and mechanically stimulated. The effects of HT7 on cocaine locomotion were then compared among control (cocaine only), superficial (1mm) and deep (3 mm) acupuncture. There was no difference between the two groups in inhibition of cocaine locomotion , indicatth digit innervated by the ulnar nerve was mechanically stimulated  after needle insertion. Which produced nearly identical effects as HT7 MAI stimulation shown in To determine which peripheral nerve conveyed the acupuncture effects of HT7 stimulation, peripheral nerves innervating the forearm were selectively transected near the elbow 48~72 hours before the acupuncture experiment and the rats were subjected to cocaine treatment followed by acupuncture at HT7. Sectioning the radial and median (Rad/Med+HT7) nerves did not affect the acupuncture effects of HT7, whereas severing the ulnar nerve (Ulnar+HT7) completely blocked MAI HT7 stimulation , providiTo determine which fiber groups were activated by HT7 MAI stimulation, single-unit recordings were made from 25 somatic afferents  during MAI stimulation of HT7. Although Aβ-fibers responding to mechanical stimulation of HT7 area were recorded easily, we found only 1 Aδ fiber or 10 C-fibers innervating HT7 from 5 rats. One Aδ-fiber recording was excluded from statistical analysis. Compared to basal activity (2.94 ± 0.87 impulses/sec), MAI stimulation at HT7 significantly increased the frequency of Aβ-fiber discharge activity . The size distribution of C8 or T1 DRG neurons labeled by injecting DiI into HT7 showed that DiI-labeled neurons from HT7 are higher in percentage of medium- or large- DRG neurons than those of adjacent muscle and total DRG neurons . Most DR2) at HT7 or whether mechanical stimulation to HT7 at high (200 Hz) or low (50 Hz) frequency reduced cocaine locomotion. Pacinian fibers (n=9) that responded to high frequency stimulation with a tuning fork (256 Hz) were isolated as described previously [Finally, to investigate which types of peripheral receptor of A-fiber, Pacinian or Meissner corpuscles, initiate the acupuncture effects, it was tested whether Pacinian or Meissener corpuscles were activated by MAI stimulation  stimulation associated with HT7 acupuncture activates both Pacinian and Meissner corpuscles and the signals of acupuncture are conveyed via large A-fibers in the ulnar nerve, which produce the inhibitory effects on cocaine locomotion. Mechanical stimulation of HT7 suppressed cocaine-induced locomotion in a time-dependent manner. The HT7 effects were produced by either superficial or deep stimulation to HT7 and also inhibited by local anesthetic around HT7 points. The HT7 effect was blocked by severing the ulnar nerve and mimicked by stimulation of 5The use of acupuncture in oriental medicine traces back to several thousand years and has been used successfully to treat various conditions. Historically, acupuncture needles are manually stimulated by the hand of the acupuncturist. Over the past several decades, manual acupuncture (MA) has been substituted with electroacupuncture (EA), since EA has the advantage of better control of stimulation frequency and intensity, resulting in high reproducibility and lower individual variations among physicians . While aAcupuncture effects may be mediated through neuronal or traditional Qi energies ,26,30. Ith digit, which is innervated by ulnar nerve [th digit caused a similar response to HT7 MAI stimulation may also suggest that the nerve, not acupoints along the nerve, is important in producing specific responses. It is still controversial what types of afferent nerve fibers are activated by MA or EA. For example, Guowei et al. suggest that the afferent signals from acupuncture at ST36 for producing analgesia are conveyed through A-fibers of the perineal nerve [Acupuncture suppression of cocaine-induced locomotor activity was completely abolished after severing the ulnar nerve and mimicked by mechanical stimulation inserted into the tip of the 5ar nerve . This isar nerve ,36, and ar nerve ,37. It sal nerve . Our preal nerve . It has al nerve  and blocal nerve , suggestWhich receptors of large A-fibers might initiate afferent signals during MA to produce the inhibitory effects on cocaine locomotion? Vibration stimuli are transmitted by two main types of mechanoreceptors, Pacinian and Meissner corpuscles that differ in physical properties and anatomical location. Pacinian corpuscles are most sensitive to high frequencies of 200 Hz, whereas Meissner corpuscles are responsive to lower frequencies around 10~50 Hz. Pacinian corpuscles are found in the deep subcutaneous tissues, the tendons of the muscles and the ligaments of joints, while Meissner corpuscles are located in the superficial portion of the dermis ,40. In t


Community-based programs aimed at improving cooking skills, cooking confidence and individual eating behaviours have grown in number over the past two decades. Whilst some evidence exists to support their effectiveness, only small behavioural changes have been reported and limitations in study design may have impacted on results.This paper describes the first evaluation of the Jamie Oliver Ministry of Food Program (JMoF) Australia, in Ipswich, Queensland. JMoF Australia is a community-based cooking skills program open to the general public consisting of 1.5 hour classes weekly over a 10 week period, based on the program of the same name originating in the United Kingdom.A mixed methods study design is proposed. Given the programmatic implementation of JMoF in Ipswich, the quantitative study is a non-randomised, pre-post design comparing participants undergoing the program with a wait-list control group. There will be two primary outcome measures: (i) change in cooking confidence (self-efficacy) and (ii) change in self-reported mean vegetable intake (serves per day). Secondary outcome measures will include change in individual cooking and eating behaviours and psycho-social measures such as social connectedness and self-esteem. Repeated measures will be collected at baseline, program completion (10 weeks) and 6 months follow up from program completion. A sample of 250 participants per group will be recruited for the evaluation to detect a mean change of 0.5 serves a day of vegetables at 80% power (0.5% significance level). Data analysis will assess the magnitude of change of these variables both within and between groups and use sub group analysis to explore the relationships between socio-demographic characteristics and outcomes.The qualitative study will be a longitudinal design consisting of semi-structured interviews with approximately 10-15 participants conducted at successive time points. An inductive thematic analysis will be conducted to explore social, attitudinal and behavioural changes experienced by program participants.This evaluation will contribute to the evidence of whether cooking programs work in terms of improving health and wellbeing and the underlying mechanisms which may lead to positive behaviour change.ACTRN12611001209987.Australian and New Zealand Trial registration number:  Cooking skills programs have been described as a practical illustration of how to simultaneously change knowledge, attitudes and behaviours around healthy eating practices . InteresIn the past two decades, there has been an increase in the number of not-for-profit community-based cooking skills programs both in Australia and internationally -8. Such Whilst there is emerging evidence of the effectiveness of these adult programs in terms of increasing confidence to cook and creating positive dietary change, this evidence, to date, has been based on small scale evaluations that are subject to methodological limitations . In a reThis methods paper describes the evaluation framework and design for the Jamie Oliver Ministry of Food program (JMoF) Australia, Ipswich site. The JMoF program was originally developed by Jamie Oliver, a renowned celebrity chef and food author based in the United Kingdom (UK). JMoF Australia has been specifically adapted for the Australian setting. It is a community focused program that teaches basic cooking skills and good nutrition to non-cooks. It consists of 10, weekly, 1.5 hour cooking skills classes aimed at getting people of all ages and backgrounds cooking simple, fresh, healthy food quickly and easily . ParticiJMoF was pioneered as a community-based cooking skills program in Rotherham, UK in 2008 and since then, other centres have opened in Bradford and Leeds and a mobile centre in the North West of the UK. These centres were reliant on funding mostly from local councils and to a lesser extent, charities and the private sector. The first Australian site opened in Ipswich in the state of Queensland in April 2011 co-funded by a local philanthropic non-government organisation (NGO), The Good Foundation (TGF), and the Queensland Department of Health. Ipswich was intentionally chosen given its significant low socio-economic status population  and incrConsultation occurred between TGF, Queensland Health (as program co-founder) and the program evaluation team to describe program objectives of the JMoF program Australia in sufficient detail to be tested in an applied evaluation. The following program objectives resulted:1. To provide opportunities, to people of different age and demographic background, to experience and learn how to cook healthy meals quickly and cheaply.2. To increase program participants’ cooking skills, knowledge and self-efficacy.3. To increase program participants’ enjoyment of food and social connectedness.A program logic model was developed as a framework to describe the potential pathways to behaviour change, and in turn to guide evaluative enquiry Figure . Whilst Theoretical frameworks were not explicitly stated for the JMoF Program. However, Carahar and Lang, 1999  have ideOther theories that resonate with the program include Kolb’s concept of experiential learning  which idThe evaluation will be conducted over a 2.5 year period from late 2011 to early 2014. The evaluation was approved by the Deakin University Human Research Ethics Committee (HEAG-H 117_11) in October 2011. Evaluation project governance will be provided by a reference group (comprising personnel from the TGF team and the research team members) which will meet twice yearly to oversee the project. A representative from Queensland Health will be invited to attend Reference Group meetings, when appropriate.The evaluation will use a questions-oriented approach  derived The quantitative component of the evaluation will answer the following research questions:1. Does the JMoF program increase participants’ skills, knowledge, attitudes, enjoyment and satisfaction of cooking and cooking confidence (self-efficacy)?2. Does the JMoF program result in broader positive outcomes for participants in terms of behaviour change to a healthier diet, more affordable healthy meals, improved self-esteem and social connectedness?There will be two primary outcome measures: a change in cooking confidence (self-efficacy) and a change in self-reported mean vegetable intake (serves per day). Secondary outcome measures will include change in self-reported measures of: (i) mean daily fruit intake, (ii) mean weekly takeaway/fast food intake, (iii) frequency of cooking the main meal from basic ingredients, (iv) nutrition knowledge, (v) attitudes towards cooking, (vi) willingness to try new foods and (vii) enjoyment and satisfaction of cooking. Change in psycho-social measures such as (viii) global self-esteem and (ix) social connectedness in relation to cooking and eating will be measured as will (x) a change in participant’s total expenditure on food.A quasi-experimental pre-post design will consist of an intervention group of participants undergoing the JMoF program and a control group comprising of participants from the program waitlist who are waiting for at least 10 weeks until program entry. Recruitment to each group will be based on program start date and will not be subject to randomisation. Randomisation was not possible as it would not allow participants any choice as to when and with whom they participated in the program – which are important aspects of the JMoF program design .Intervention participants will be surveyed at three time-points: program commencement, program completion (10 weeks) and at six months post program completion. Controls drawn from the waitlist will be surveyed at two time-points: 10 weeks prior to program commencement and on completion of their 10 weeks on the waitlist (which will correspond to their program entry). A time-three measurement will not be obtained from controls as it was considered neither feasible nor acceptable for the waitlist controls to have to wait a further six months before entering the program ; this potentially would lead to a high drop-out rate both from the evaluation and the program itself. However, for one of the primary outcome measures, vegetable intake, Queensland state-wide monitoring data will be used as a proxy time-three measure for the control group.In collaboration with key stakeholders, a quantitative measurement tool was developed. The self- administered questionnaire was designed to be completed in approximately 15 minutes. Given the lack of validated and reliable survey tools which can accurately measure the impacts and outcomes of cooking skills programs in varying population groups , a protoTo measure the primary outcome of cooking confidence as a proxy for cooking self-efficacy, questions were developed addressing confidence in relation to specific cooking skills based on Short’s work  and BartThe other primary outcome measure of change in vegetable intake will be captured through self-report questions of vegetable intake (serves per day) and aligned with baseline measurement questions of the same nature used by Queensland Health in its population-based self-reported health surveys . Survey Other secondary outcome items include measuring change in the self-reported frequency of cooking the main meal from basic ingredients and the inclusion of salad or vegetables with the main meal. Nutrition knowledge questions, aligned with the nutrition messages embedded within the program, will test knowledge around salt, fat and sugar intake and have been adapted from Parmenter et al’s work .Participant attitudes towards cooking and eating healthy foods, willingness to try new foods, enjoyment and satisfaction in cooking and eating healthy foods will be tested, using Likert scale based questions. Questions about shared enjoyment of cooking, eating and normative eating behaviours were adapted from questions from The Stephanie Alexander Kitchen Garden Evaluation (SAKG) . The RosParticipants will be asked to report their total household food and drink  expenditure and expenditure specifically on take-away food and fruit and vegetables. Height and weight will be self-reported to enable the calculation of Body Mass Index (BMI).The questionnaire was piloted in a 3 step process to test the design, content and potential delivery methods. Following comment by the reference group and academic colleagues on content and layout/design, a paper-based version of the questionnaire was piloted with a sample (N = 30) of the current JMoF population. Feedback was invited through informal focus group sessions, facilitating the identification of any questions that were ambiguous, sensitive or required further development.The final stage of piloting involved testing the questionnaire in an online format whilst simultaneously testing the online survey distribution system and the likely response rate. As the survey distribution required integration between the JMoF participant database and the survey platform, Qualtrics™ , the pilAll participants registered on the JMoF Australia waitlist database, aged 18 years or over, and who had received a confirmed start date for the program, will be eligible to participate in the quantitative component of the evaluation. Whilst the program is open to all members of the Ipswich community over the age of 12 years, the evaluation will target the adult population only as other cooking skills programs exist within the Greater Ipswich region that are specifically targeting children and adolescents in educational settings.All participants will be required to consent prior to participation in the evaluation. A link to the questionnaire will be embedded within an email generated by the JMoF program database, inviting program participants to participate in the evaluation questionnaire.Recruitment to both groups will be based on confirmed program start dates. As control participants are required to be on the program waitlist for 10 weeks and because the JMoF waitlist is sufficiently large to enable this to occur naturally, participants that are allocated a start date longer than 10 weeks ahead, will be automatically made a control, whilst persons commencing the program within 10 weeks will be assigned to the intervention group. Computer programmed “rules” in the JMoF participant database have been created to automate this process.To show appreciation for participation, those intervention participants who complete the third and final questionnaire at six months post completion of the program will be sent a $20 “Good Guys” store charge card redeemable at any Good Guys store (white goods retailer) across Australia.Data collection commenced in February 2012 following completion of piloting. Whilst the challenges of delivering online surveys are well documented , it was Given that the specific questions developed for this study to measure confidence to cook (cooking self-efficacy) have not been previously employed, a precise sample size calculation for this primary outcome could not be calculated given the absence of a priori baseline measures, measures of effect size and measures of variance (standard deviation).Sample size calculations around the second primary outcome of a change in vegetable intake between the two groups assumed the use of a split-plot anova and F test for interaction given the wait list design. The literature does not provide clear guidance with regards to an expected effect size for a program of this nature ,30. HoweDemographic and baseline characteristics will be summarised for both intervention and control groups using standard summary statistics (mean and standard deviation) and non-parametric statistics (medians and inter-quartile ranges) where applicable. Frequencies and percentages will be reported for categorical variables. The magnitude of change both within and between intervention and control groups for T1, T2 and T3 time-points will be assessed. For continuous data, such as fruit and vegetable intake, two sample t tests will be employed to compare means between intervention and control groups at each time point and paired t tests for within group comparisons. A split-plot in time Anova will be used as the basis for these t-tests. For categorical data, frequencies will be reported for intervention and control groups and chi squared analysis will provide between group comparison results. Regression analysis will be conducted to determine the potential contribution of specific demographic factors on the outcome variables of interest. All data analysis will be performed using STATA S.E. 12.0 statistical software.To further understand how and why the JMoF program impacts on participants, the qualitative investigation will explore the following:1. What are the expectations and experiences of participants?2. What are the moderators, facilitators and barriers to behaviour change?3. Were there any unanticipated outcomes?A longitudinal design will be employed for the qualitative study to follow program participants over the course of their JMoF journey. This will allow for prospective accounts of a participant’s experience and change over time ,32. RepeThe interview structure was generated to capture participant perspectives, to explore moderators, facilitators and barriers to behaviour change, and to capture any unanticipated outcomes from program involvement. As indicated in Table Interviews of approximately 30-40 minutes duration will take place in a public location that provides a comfortable environment for both interviewer and the participant. All interviews will be conducted by the same researcher and participants will be required to consent to both participation and recording of the interview. To show appreciation for participation in an interview, participants will be thanked with a $15 Coles supermarket gift voucher at each interview.Purposive sampling will be employed initially to capture maximum variation  in factoParticipants who have completed the baseline quantitative study survey and have agreed to be contacted for an interview, will be eligible to participate as well as all participants who are within the first three weeks of commencing the program. The baseline survey data will assist in purposive selection for the qualitative interviews, using the criteria based on demographic and personal circumstances as previously described. Opportunistic purposive sampling will also be carried out during the researcher’s time in Ipswich during class observations. Selected participants will be contacted by phone or in person (in class context) and provided with information about the qualitative component of the study and invited to participate in the interviews. Written consent will be required prior to participation in the interview process.The interviews will be transcribed verbatim. The data will be managed with the assistance of qualitative software package NVivo 9 . Concurrent data collection and analysis will be conducted to allow for confirmation of emerging themes and clarification of any contradictory findings . To contThe analysis of interview transcripts and interview memos will be conducted by the interviewer using inductive thematic analysis. The data will first be coded and then categorised to allow themes and patterns to emerge ,36. A seIn addition to the separate analysis of the quantitative and qualitative results, integration of the respective findings will be conducted. This will involve examining consistencies and inconsistencies in the findings from each method ,38 to buThe evaluation of the JMoF program will contribute to the growing body of literature on the effectiveness of community-based cooking skills programs. It will employ a mixed methodology to draw on the strengths of both quantitative and qualitative study design to best capture and measure experiences, impacts and outcomes of cooking skills programs. The methods described herein will inform the research community about program outcomes and facilitate comparisons of results with other cooking skills programs conducted in comparable populations.This study will also provide insights into practical considerations required when designing program evaluations in community settings. These include factors such as recruitment of a comparison group, minimisation of participant data collection burden, and the suitability and feasibility of selected data collection modes, which must be considered without compromising study design or program integrity.There are both strengths and limitations to the evaluation design. Mixed methods studies as a paradigm can risk compromising methodological rigour if integration occurs at point of data collection and/or analysis and potentially undermines paradigm and process considerations ,19. ThisWhilst it is acknowledged that the use of a non-randomised quasi-experimental design makes the quantitative study vulnerable to sampling bias, practical limitations prevented the application of a randomised design. Despite this potential bias, the use of a waitlist control and pre and post measures support attribution of any changes to the program.Potential selection bias associated with choice to participate or not in the quantitative study may also occur. However various methods were employed in an attempt to address this issue: providing participants with multiple options for survey completion, follow up of non-responders and the use of incentives.In the quantitative study, there is no direct measure of cooking skills despite the JMoF program being a cooking skills program per se. However, there is currently no gold standard for the measurement of cooking skills in an adult population nor consensus on the definition of cooking skills or whether changes in it alone will predict the likelihood of changes in cooking behaviour . TherefoIn summary, the use, in this evaluation, of a mixed method, pre-post design with a waitlist control group will provide sufficient strength of evidence to assess the impact of the JMoF program on participants’ attitudes and behaviours. It will also make a contribution to the limited evidence base about the effectiveness of community-based cooking programs.The authors wish to declare that the evaluation has been commissioned by The Good Foundation.All authors have contributed to project design and development, whilst AF and JH are responsible for project management and data collection. AF drafted the manuscript with JH and LG contributing to the qualitative sections. All listed authors reviewed the draft manuscript, then read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/411/prepub


It has recently been observed that elevated levels of IgM HLA antibodies also correlates with the development of chronic rejection in heart and kidney transplantation. This study investigates the relationship between IgM and IgG antibodies against HLA and MICA after lung transplantation. Serum was collected from 49 patients once prior to transplantation and monthly for up to 1 year after lung transplantation was analyzed by Luminex to detect IgM and IgG antibodies against HLA and MICA. The presence of either IgM or IgG HLA and/or MICA antibodies prior to or after transplantation was not related to survival, gender, primary disease, or the development of BOS. Additionally, the production of IgG alloantibodies was not preceded by an increase in levels of IgM, and IgM levels were not followed by an increase in IgG. Under current immune suppressive regimen, although the presence of IgM antibodies does not correlate with BOS after LTx, IgM The bronchiolitis obliterans syndrome (BOS) represents chronic rejection that accounts for the majority of mortality after lung transplantation (LTx). Almost 50% of lung transplant recipients develop BOS within five years after LTx –3. BOS cThe presence of IgG anti-HLA in patient sera reactive with antigens present on the donor lung prior to transplantation is a contraindication for transplantation , 10. TheThe goal of this study was to determine the relationship between IgM HLA antibodies after lung transplantation and the development of BOS. Additionally, we examined whether a correlation existed between IgM and IgG HLA antibodies after lung transplantation to determine if the isotype switch is inhibited by the immune suppressive regimen of tacrolimus/mycophenolate mofetil.1 of more than 20% compared to the postoperative baseline in the absence of infection or other etiology [1 decline, patients were treated with corticosteroids and azithromycin.A total of 49 LTx patients transplanted between September 2003 and March 2008 at the Heart Lung Centre in Utrecht, The Netherlands, who exhibited a greater than three months survival, were included in this study. Eleven patients developed BOS during followup. BOS was defined as an irreversible decline in FEVetiology , 15. StaThe study design was approved by the medical ethical committee. Informed consent was obtained from each patient. Patients donated blood every month during the first year after transplantation and once every three months in the following years.Sera of 49 patients with known HLA type were screened for the presence of anti-HLA and anti-MICA antibodies prior to transplantation and then longitudinally, with an average of 20.7 months (range 10–29 months), after transplantation. A total of 382 samples were analyzed for IgG, and 477 samples were analyzed for IgM antibodies against HLA using Luminex beads according to the manufacturer's protocol . For the IgM assay, the IgG detecting antibody was replaced with an IgM detecting antibody (R-phycoerythrin-conjugated AffiniPure F(ab) Fragment Donkey anti-human IgM obtained from Jackson ImmunoResearch). Three hundred eighty-two samples obtained from 49 patients were analyzed for both IgG and IgM.The IgM tests were validated by measurement of 30 unimmunized males and measurements of samples obtained from kidney transplantation patients known to have high titers of IgM using both ELISA and Luminex. Optimal serum dilutions, conjugate dilutions, and incubation times were determined.Dithiothreitol (DTT) was used to deplete serum IgM as previously described . Sera wePositivity for IgG anti-HLA or -MICA was defined using the default settings of the software (Fusion) provided by the manufacturer (One Lambda). For IgM-positive HLA and MICA antibodies, a threshold was defined. Thirty healthy HLA-unimmunized males were analyzed to determine background levels. For each bead, the average background, including the range and standard deviation, was determined in these healthy controls. A patient was considered to have positive antibodies when the mean fluorescent intensity (MFI) (corrected for the negative bead) was >5 times the average background MFI of the unimmunized males.high/IgMlow when MFI values were above or below the overall average of all beads in thirty healthy HLA-unimmunized males or IgGhigh/IgGlow when MFI levels were above or below the average background levels of all beads for IgG as defined by the manufacturer.Titers of IgM and IgG antibodies were defined as IgMFor each patient, it was determined which beads contained at least 1 antigen from a mismatched donor HLA. These beads were considered to possess possible donor-specific antigens (DSA). Beads that were negative for mismatched donor HLA antigens were identified as third-party antigens (TPA).P value of < 0.05 was considered to be significant. For correlation analysis, a P value of < 0.05 combined with −0.4 ≤r≥ 0.4 was considered significant. Correlations were analyzed using spearman rank correlation analysis, and differences in patient characteristics were analyzed by Mann-Whitney rank-sum, Fisher exact, or chi-square tests. These tests were also used to analyze differences in IgM and IgG titers between patients with and without BOS.A P = 0.02, Fisher exact test). It should be noted that the group of BOS patients did not differ from the patients without BOS with respect to gender, age, primary disease, type of graft, ischemic time, or HLA mismatches for class I and class II. The average onset of BOS was 22.5 months after lung transplantation.This study involved 49 patients whose details are displayed in n = 7) compared with the IgG (n = 2) isotype. After transplantation, serum was collected monthly from 49 patients. It was observed that antibodies against HLA class I and/or class II were more frequently of the IgG (n = 23) isotype than of the IgM (n = 16) isotype. MICA antibodies, however, were more frequently of the IgM (n = 14) isotype . No relationship was observed between presence of antibodies before and after lung transplantation. The majority of patients who, prior to LTx, have antibodies against HLA or MICA also express these antibodies after transplantation. Some of these antibodies are not persistently reactive with the same HLA-coated Luminex beads, and some patients expressing antibodies prior to LTx do not express them after LTx. In 25 patients, de novo antibodies against HLA or MICA appeared after transplantation, with an average first appearance after transplantation at 7.5 months (HLA class I), 17.6 months (HLA class II), and 8.4 months (MICA). A longitudinal analysis was performed to determine if specific patterns in the elevation or reduction of titers could be observed. Although, on average, low but stable titers of HLA class I, class II, and MICA IgM antibodies were detected after LTx, average titers were elevated compared to background titers . Given these findings, the lack of IgG anti-HLA detection in serum samples with IgM anti-HLA antibodies is not the result of inhibition by antibodies of the IgM isotype.In samples containing elevated levels of IgM or IgG antibodies against HLA, it was investigated whether high IgM was followed in time by high IgG or whether high IgG was preceded by high IgM. To this end, beads were identified recognized by patient sera and the other sera collected from the same patients at other time points were analyzed for reactivity against the same beads. P = 0.09, fisher exact test). Patients lacking IgM antibodies were younger than patients expressing MICA IgM antibodies . Transplant patients suffering from end-stage cystic fibrosis prior to LTx were younger than patients diagnosed with emphysema or fibrotic diseases. These cystic fibrosis patients exhibited reduced levels of IgM antibodies compared to the other patients  and, also, showed a reduction in HLA class I and/or class II IgM antibodies . These differences in clinical characteristics in patients with and without IgM antibodies were not observed after lung transplantation.We next investigated if clinical characteristics were related to IgM or IgG anti-HLA antibodies present prior to lung transplantation. There was no difference in the gender of patients that tested positive for IgM or IgG isotype HLA antibodies prior to transplantation. The percentage of males expressing IgM antibodies against MICA prior to transplantation was slightly higher than that of females . To examine whether differences observed between BOS and non-BOS patients were correlated with antibody titers, all data points were plotted in separate correlation graphs. We observed that the majority of the samples obtained from patients eventually diagnosed with BOS were below IgG background levels . Differences in IgG antibody titers were more defined, with only 14% of BOS patients exhibiting elevated IgG antibody titers versus 54% of the samples from non-BOS patients . For HLA class II, there was no observable difference between BOS and non-BOS patients. Analysis using DSA and TPA coated beads also did not indicate any differences. In Figures Analysis of antibody titers after LTx indicated no relationship to the development of BOS (data not shown), as no rise or fall in antibody titers was observed prior to BOS diagnosis. The presence of IgM or IgG antibodies against HLA class I, HLA class II, and/or MICA prior to or after lung transplantation is not related to the development of BOS. Donor-specific antibodies may better correlate with development of BOS, so we designated DSA for beads with possible donor-specific antigens and TPA beads lacking these antigens. Our results indicated no differences between patients with BOS and without BOS for IgM anti-HLA, although a trend was observed in patients lacking IgG anti-HLA, as they developed BOS with a higher frequency (d levels , while ed levels . By contd levels  comparedd levels . To quanIn this study, we demonstrate that the presence of IgM HLA and MICA antibodies prior to or after lung transplantation is not related to the development of BOS. We also show that the course of IgM antibody titers is stable after lung transplantation. After LTx, there is no correlation between IgM and IgG antibodies, as high IgM is not followed by high IgG and high IgG is not preceded by IgM. Patients diagnosed with BOS, however, do exhibit elevated HLA class I IgM antibody titers and low IgG titers compared to patients without BOS.IgM antibodies against HLA have been considered to be clinically irrelevant, but recent findings challenge this concept. In heart transplantation, it was shown that non-HLA antibodies of IgM isotype were correlated with a reduction in graft survival , 17. In One study detected a correlation between MICA antibodies and development of rejection after kidney transplantation. However, a number of other studies of heart or kidney transplantation did not find such a relation –22. Althhigh antibody titers in BOS patients is not an artifact caused by high concentrations of IgM antibodies. Elevated levels of IgG anti-HLA that are detected after lung transplantation are also commonly observed prior to transplantation. The production of these antibodies is therefore not hampered by the immunosuppressive treatment with tacrolimus and mycophenolate mofetil administered after transplantation. We also observed no indication of IgM replacement by IgG alloantibodies, suggesting a lack of class-switching of B cells that may be due to the immunosuppression of T cells. These findings revealed that de novo IgG anti-HLA antibodies after lung transplantation yielded low levels of MFI.High levels of IgM antibodies in serum may physically inhibit the binding of IgG antibodies to the Luminex beads ; howeverhigh IgGlow antibodies are elevated in patients with BOS, this cannot be used as a possible marker for the development of BOS because some patients without BOS also have antibody titers exhibiting elevated IgM and low IgG. Additionally, although patients without BOS express higher HLA IgG antibody levels compared to patients with BOS, some considerations have to be placed. First, HLA IgG antibody titers are low and may not be capable of activating the complement cascade. Second, it is unknown if IgG HLA antibodies are of the IgG1, IgG3 subclasses able to fix complement, or of the IgG2 and IgG4 subclasses. If HLA antibodies are sequestered to the transplanted lung rendering them undetectable in BOS patients, they could fix the complement system and hence contribute to the development of BOS after lung transplantation [Although titers of HLA class I IgMantation , 24, 25.antation , 26. It In conclusion, lung transplant patients develop IgM HLA and MICA antibodies prior to and after transplantation. The presence of these antibodies and their titers are not related to chronic rejection under the current immune suppressive regime, and the isotype switch is inhibited. Patients diagnosed with BOS, however, exhibit elevated levels of IgM and reduced IgG HLA expression compared to patients without BOS. HLA antibodies are thought to be involved in chronic graft rejection as a result of their complement fixing ability as observed by C4D deposition within the graft. Mechanistically, our data could imply that IgM HLA antibodies are relevant to the pathogenesis of BOS because they are able to fix complement more efficiently than IgG.