Early secondary outcome analysis in multi-phase randomised-controlled trials, a pragmatic approach: the Healthy Life Trajectories Initiative (HeLTI).

OBJECTIVES/SPECIFIC AIMS:. The study aims to understand the characteristics of junior investigators who are supported by the CTSI, their knowledge of CTSI services and resources, as well as the perceived effectiveness of CTSI research training and career development. The primary outcome is scientific productivity that enhances career development and promotion. The secondary outcome is to inform and improve CTSA research training and career development, not only for the UCLA CTSI hub but also for the CTSA Program nationally. METHODS/STUDY POPULATION:. The study sample includes post-doctoral and junior investigators who have received UCLA CTSI support between 2011 and 2017 (n=319). These junior investigators conduct research at our four partner sites (UCLA-Westwood, Cedars-Sinai Medical Center, The Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Charles R. Drew University of Medicine and Science). The CTSI administered the LSAS and the Career Development module in 2018 using Qualtrics, a subscription software for collecting and analyzing survey data. In order to reduce the burden on the survey respondents, the survey team pre-populated their previously reported publication in the Qualtrics survey system. Qualtrics sends customized email invitations containing a link to start the LSAS survey and subsequently automated sequences of reminder messages for non-responders and partial completers. The survey team initiated telephone call-backs and engaged partner site leaders to achieve a high response rate. RESULTS/ANTICIPATED RESULTS:. Preliminary results show a response rate of 83% (n=264). Respondents include K-to-R workshop participants (n=192), core voucher co-investigators (n=38), Training Program in Translational Science (TPTS) trainees (n=82), and junior investigators who participated in two or more of these activities (n=48). Trainee characteristics include degree, gender, and partner site location. The distribution of advanced degrees among the junior investigators include: PhD (29%), MD (55%), MD/PhD (13%), or other degree (3%). Forty-four percent (44%) respondents are male and 56% are female. Seventy-two percent (72%) have a primary appointment at UCLA-Westwood, while 28% have academic appointments at the partner institutions. Twenty-five percent (25%) received CTSI research training and 49% received CTSI career development support. Regarding scientific productivity, 58% reported having at least one peer-reviewed publication and 29% reported subsequent grant funding. DISCUSSION/SIGNIFICANCE OF IMPACT:. We are in the process of identifying the predictors of scientific productivity and the characteristics of the junior investigators most significantly correlated with productivity using multiple logistic regression analysis. We will analyze qualitative responses to examine the facilitators and barriers to conducting research at the CTSI and explore ways to improve administrative and clinical research processes. The significance of this research is to inform research training and career development programs within our CTSA hub and the CTSA Program nationally.

BackgroundAdverse outcomes occurring early after antiretroviral therapy (ART) initiation are common in sub-Saharan Africa, despite reports of high levels of ART adherence in this setting. We sought to determine the relationship between very early ART adherence and early adverse outcomes in HIV-infected adults in Botswana.MethodsThis prospective cohort study of 402 ART-naïve, HIV-infected adults initiating ART at a public HIV clinic in Gaborone, Botswana evaluated the relationship between suboptimal early ART adherence and HIV treatment outcomes in the initial months after ART initiation. Early adherence during the interval between initial ART dispensation and first ART refill was calculated using pill counts. In the primary analysis patients not returning to refill and those with adherence <0.95 were considered to have suboptimal early adherence. The primary outcome was death or loss to follow-up during the first 6 months of ART; a secondary composite outcome included the primary outcome plus incident opportunistic illness (OIs) and virologic failure. We also calculated the percent of early adverse outcomes theoretically attributable to suboptimal early adherence using the population attributable risk percent (PAR%).ResultsSuboptimal early adherence was independently associated with loss to follow-up and death (adjusted OR 2.3, 95% CI 1.1–4.8) and with the secondary composite outcome including incident OIs and virologic failure (adjusted OR 2.6, 95% CI 1.4–4.7). However, of those with early adverse outcomes, less than one-third had suboptimal adherence and approximately two-thirds achieved virologic suppression. The PAR% relating suboptimal early adherence and primary and secondary outcomes were 14.7% and 17.7%, respectively.ConclusionsSuboptimal early adherence was associated with poor outcomes, but most early adverse outcomes occurred in patients with optimal early adherence. Clinical care and research efforts should focus on understanding early adverse outcomes that occur despite optimal adherence.

Background. Several randomized trials demonstrated aromatase inhibitors (AI) superiority in terms of disease-free survival (DFS) compared to tamoxifen treatment for postmenopausal hormone receptor-positive breast cancer (BC) patients. Anyway, AI toxicity profile is a concern due to estrogen suppression. Pivotal trials demonstrated a significant bone mineral density (BMD) loss due to AI, with a consistent 5-year risk of bone fractures, thus impacting on patients' quality of life. Bisphosphonates represent an effective treatment in postmenopausal osteoporosis fractures prevention. However, an adequate patient's selection for adjuvant bisphosphonates treatment during AI endocrine therapy is still a challenge. Final results of BONADIUV trial presented at San Antonio Breast cancer Symposium in 2016 showed that treatment with ibandronate, as compared to placebo, significantly improved BMD change in osteopenic women treated with adjuvant AI, and consistently protected patients' bone loss. We present the secondary 5-year analysis on survival outcomes of the trial. Patients and methods. The BONADIUV trial is a single-blind, randomized, placebo-controlled phase 2 study designed to evaluate the impact of ibandronate treatment on BMD in osteopenic women taking AI. Between January 2011 and May 2014, 171 osteopenic patients (lumbar spine [LS] and/or trochanter -1&amp;lt; T-score &amp;lt;-2.5), were randomized in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). Treatment duration was 2 years, with 6-months evaluation. Primary endpoint was the mean BMD difference between the two arms at a 2-year follow up. Secondary analysis on survival outcomes (overall survival [OS] and invasive DFS [iDFS]) have been performed at 5-year median follow-up time. ClinicalTrials.gov identifier: NCT02616744. Results. At the database cutoff time for the present analysis on May 4, 2018, median follow up was 63.3 months (mean 61.2; range 2.7-87.3) for whole series, 64.9 months (range 33.8-84.0) for the placebo arm, and 62.2 months (range 24.2-87.3) for the ibandronate arm. Ten patients in the placebo group and 17 patients in the ibandronate group withdrew the allocated arm before any follow up data collection, and so were excluded from the analysis, performed on 144 patients (72 patients per arm). At the database cutoff time, the OS rate was 97.2% in the placebo group and 100% in the ibandronate arm. We observed four loco-regional relapse (three in the placebo arm, one in the ibandronate arm; p=0.33), three distant metastases (none in the placebo arm, three in the ibandronate arm; p=0.075), and three contralateral BC (one in the placebo arm, two in the ibandronate arm; p=0.65). The number of iDFS events did not differ between groups: four in the placebo group and six in the ibandronate group (p=0.56). Up to data cutoff, two deaths have occurred; none in the placebo arm and two in the ibandronate arm (p=0.15). The OS rate did not differ between arms. Conclusions. The secondary analysis of survival outcomes showed no difference between arms in terms of OS and iDFS rates. Further large investigations and mature follow-up from the published ones are awaited. Citation Format: Meattini I, Scotti V, Desideri I, Saieva C, Visani L, Salvestrini V, Cecchini S, De Feo ML, Mariotti M, Olmetto E, Delli Paoli C, Francolini G, Bernini M, Orzalesi L, Sanchez L, Nori J, Bianchi S, Livi L. Oral ibandronate for osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: secondary 5-year survival outcomes analysis of the single-center phase 2 BONADIUV trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-04.

The purpose of effectiveness assessment is to assist health care providers and patients to make informed decisions that will improve health care. How to assess the effectiveness of Chinese medicine (CM) scientifically is a critical issue and needs to be resolved. We summarize the advances in outcome research into the effectiveness assessment of CM in this chapter. For principles of effectiveness assessment, we need to select outcome measures according to the research purpose and synthetically consider evidence of randomized controlled trials and well-designed observational studies. The outcome categories include primary outcome, secondary outcome, composite outcome, surrogate outcome, and patient-reported outcomes (PROs). The advantages, disadvantages, and function comparison of primary and secondary outcomes should be identified. Composite outcomes are often applied to clinical trials in case of unavailable or impractical primary outcomes. The composite outcomes can also capture the multidimensional nature of disease, seek a comprehensive response to intervention, and thus could be especially important for complex intervention including CM. The development and validation of a composite outcome should be through rigorous scientific research design and statistical model. When the secondary outcome is confirmed to be associated with the true clinical outcome and completely reflect the net effect of treatment on the outcome, this secondary outcome can also be the surrogate outcome. Although the definition of the surrogate outcome has been proposed, the application is limited currently. PROs are supposed to highlight the features and superiority of CM in clinical effectiveness assessment. Developing a new PRO instrument based on CM treatment nature by the standard procedures is feasible to be commonly recognized and accepted in biomedicine. Based on the integration of domestic and foreign research view in recent years, we systematically describe both retrospective and prospective effectiveness assessment studies. Finally, we illustrate the outcome selection by examples. In summary, we must clearly recognize the differences in primary, secondary, and surrogate outcomes, and choose the appropriate outcome measures according to the study purposes, study models, and CM characteristics.

Outcome-dependent sampling (ODS) scheme is a cost-effective way to conduct a study. For a study with continuous primary outcome, an ODS scheme can be implemented where the expensive exposure is only measured on a simple random sample and supplemental samples selected from 2 tails of the primary outcome variable. With the tremendous cost invested in collecting the primary exposure information, investigators often would like to use the available data to study the relationship between a secondary outcome and the obtained exposure variable. This is referred as secondary analysis. Secondary analysis in ODS designs can be tricky, as the ODS sample is not a random sample from the general population. In this article, we use the inverse probability weighted and augmented inverse probability weighted estimating equations to analyze the secondary outcome for data obtained from the ODS design. We do not make any parametric assumptions on the primary and secondary outcome and only specify the form of the regression mean models, thus allow an arbitrary error distribution. Our approach is robust to second- and higher-order moment misspecification. It also leads to more precise estimates of the parameters by effectively using all the available participants. Through simulation studies, we show that the proposed estimator is consistent and asymptotically normal. Data from the Collaborative Perinatal Project are analyzed to illustrate our method.

What's New in Spine Surgery.

BackgroundThe aim of this study was to compare the changes in primary (heroin use-related) and secondary (depressive symptoms and quality of life, QOL) outcome indicators of 3-month methadone maintenance treatment (MMT) between heroin users with and without HIV infection.MethodsA total of 242 intravenous heroin-dependent individuals (30 with and 212 without HIV infection) receiving MMT were recruited. Primary (severity of heroin dependence, harm caused by heroin use and current heroin use) and secondary (depressive symptoms and QOL) outcome indicators were determined before and after receiving 3-month MMT. Changes in primary and secondary outcome indicators between the two groups were compared using mixed-model analysis.ResultsHeroin users both with and without HIV infection showed significant improvement in three primary outcome indicators after 3-month MMT, and there was no difference in the changes of these primary outcome indicators between the two groups. However, improvements in depressive symptoms and the physical domain of QOL among HIV-infected heroin users were poorer than in those without HIV infection.ConclusionsThe results of this study indicated that heroin users with HIV infection did improve in the primary but not the secondary outcomes after 3-month MMT.

Children with overweight or obesity are more likely to experience sleep disorders, although the role of weight in pediatric insomnia treatment has not been examined. The current study examined the relationships of high body mass with pretreatment insomnia severity and global sleep problems and the potential moderating impact of weight on changes in insomnia severity following insomnia treatment. Participants included 1,133 youth ages 2-18 years clinically referred for insomnia treatment. The Pediatric Insomnia Severity Index was collected at the initial assessment and throughout treatment as part of routine clinical care. Treatment status was coded as no treatment, early termination, and completed treatment. Secondary measures of global sleep problems at the initial assessment included the Adolescent Sleep Wake Scale, Adolescent Sleep Hygiene Scale, and Children's Sleep Habits Questionnaire. Medical chart review of visits within ± 3 months of baseline was used to obtain age-adjusted and sex-adjusted body mass index Z-score. Among adolescents, regression analyses found that higher body mass index Z-score modestly predicted baseline insomnia severity (P = .021) and worse sleep hygiene (P < .001). For children, higher body mass index Z-score was modestly associated with baseline total sleep problems (P = .006) but not insomnia severity (P = .792). Across ages, body mass index Z-score predicted neither treatment status nor insomnia improvement (P > .05). Findings were similar in categorical analyses comparing patients with overweight/obesity to healthy weight. Although there is evidence that children of higher body mass present for insomnia treatment with greater sleep concerns, body mass does not predict treatment completion or insomnia improvement. Data suggest insomnia treatment is effective irrespective of weight status. Duraccio KM, Simmons DM, Beebe DW, Byars KC. Relationship of overweight and obesity to insomnia severity, sleep quality, and insomnia improvement in a clinically referred pediatric sample. J Clin Sleep Med. 2022;18(4):1083-1091.

Edwards Intuity is recognized as a relatively contraindicated bioprosthesis for bicuspid aortic valve disease. This study compared the early echocardiographic and clinical outcomes of rapid-deployment aortic valve replacement for bicuspid versus tricuspid aortic valves. Of 278 patients who underwent rapid-deployment aortic valve replacement using Intuity at Seoul National University Hospital, 252 patients were enrolled after excluding those with pure aortic regurgitation, prosthetic valve failure, endocarditis, and quadricuspid valves. The bicuspid and tricuspid groups included 147 and 105 patients, respectively. Early outcomes and the incidence of paravalvular leak were compared between the groups. A subgroup analysis compared the outcomes for type 0 versus type 1 or 2 bicuspid valves. The bicuspid group had more male and younger patients. Comorbidities, including diabetes mellitus, hypertension, chronic kidney disease, and coronary artery disease, were less prevalent in the bicuspid group. Early echocardiographic evaluations demonstrated that the incidence of ≥mild paravalvular leak did not differ significantly between the groups (5.5% vs. 1.0% in the bicuspid vs. tricuspid groups, p=0.09), and the early clinical outcomes were also comparable between the groups. In the subgroup analysis between type 0 and type 1 or 2 bicuspid valves, the incidence of mild or greater paravalvular leak (2.4% vs. 6.7% in type 0 vs. type 1 or 2, p=0.34) and clinical outcomes were comparable. Rapid-deployment aortic valve replacement for bicuspid aortic valves demonstrated comparable early echocardiographic and clinical outcomes to those for tricuspid aortic valves, and the outcomes were also satisfactory for type 0 bicuspid aortic valves.

Preventable sources of bias in subgroup analyses and secondary outcomes of randomized trials

Discussion: On the role and analysis of secondary outcomes in clinical trials

Natural history outcome of moderate tricuspid regurgitation with preserved left-ventricular ejection fraction.

Background: Phalloplasty in transgender men is performed with or without Urethral Lengthening (UL). To create clear expectations in the choice of UL, an overview and comparison of outcomes is useful. Aims: To provide and compare surgical outcomes and urinary functioning after phalloplasty with versus without UL in transgender men. Methods: A single-center, retrospective chart review was conducted among transgender men who underwent phalloplasty with or without UL between 01-2013 and 10-2020. Primary outcomes were differences in complication and reoperation rates. Secondary outcomes were end-stages of voiding at last follow-up and differences in voiding analyses pre- and postoperatively. Results: Of 136 men, 91 (67%) underwent phalloplasty with, and 45 (33%) without UL. Wound infection (31 vs. 16%, p = 0.06) and partial flap loss (35 vs. 13%, p = 0.008) were predominately seen after UL. In the UL group, 43% urethral fistulas and 60% urethral strictures were observed, relative to one man without UL who had a urethral fistula (both p < 0.001). Meatal or perineal orifice stenosis was seen in 29% with versus 11% without UL (p = 0.02). Reoperation was needed in 81% with versus 27% without UL (p < 0.001). At follow-up, 80/91 (88%) after UL reached end-stage of voiding, with 60/80 (75%) able to void while standing and 20/80 (25%) having a definitive urethrostomy. The remaining 11/91 (12%) men were awaiting further treatment for urological complications. The men able to void while standing had a median of one reoperation (range 0–6), and a significant decrease in maximum flow rate on postoperative uroflowmetry (21.4 vs. 29.8 mL/s, p < 0.001). After phalloplasty without UL, all men had a definitive perineostomy without changes in voiding analyses. Discussion: The choice for or against UL during phalloplasty has become more relevant over the years. This comparison of surgical outcomes and urinary functioning can be useful in the shared decision-making process to come to the most suitable choice of phalloplasty.

Completion of upper secondary education marks the minimum threshold for successful labour market entry and continued employability as suggested by the Organisation for Economic Co-operation and Developments (OECD's) annual indicators on education and associated labour market outcomes (OECD, 2015). On average across OECD countries, unemployment risk of younger adults (25–34 year-olds) who have not completed upper secondary education is almost double the risk of those with higher educational qualifications (upper secondary and postsecondary nontertiary education). A maintained focus on completion rates are necessary. Even though enrolment rates among 15–16 year olds (i.e., those typically in upper secondary programmes) are high; at least 95% on average across OECD countries in 2015 (OECD, 2018); far from all students graduate. According to OECD, only approximately 75% of students who had enroled had graduated after two years. Further, of the students who had not graduated, 80% were no longer enroled in education. Many countries set specific targets for the completion rates of upper secondary education. For example, the countries in the European Union (EU) agreed on a 10-year strategy proposed by the European Commission on March 3, 2010, for advancement of the economy of the EU (Europe, 2020). One of the main targets is to reduce the share of early school leavers to 10% from the (at that time) current 15% and increase the share of the population aged 30–34 having completed tertiary from 31% to at least 40% (European Commission, 2010). Some countries go even further as, for example, Denmark, setting as a specific target, that upper secondary completion rates should be 95% and tertiary enrolment and completion rates should be 60% by 2020 (OECD, 2013a). Not only graduation rates are important, the quality of the education received also matters for the educational prospects of young people and successful entry into the labour market. The shares of neither employed nor in education or training (NEET) are negatively related to the skill levels among young people (OECD, 2017a). The OECD's Programme for International Student Assessment (PISA) tests students near the end of their compulsory education (usually around age 15) on their reading ability, their skills in math and level in sciences. In general, the higher the percentage of low-performing 15-year-old students in PISA, the higher the percentage of NEETs among 15–19 year-olds (OECD, 2017a). Having acquired some of the knowledge and skills that are essential for full participation in modern societies, particularly in reading, mathematics and science may be more reliable predictors of economic and social well-being than the number of years spent in school or in postformal education (OECD, 2016). Research based on the 2012 Survey of Adult Skills (PIAAC) finds that poor proficiency in numeracy and literacy limits access to rewarding and well-paid jobs, and in addition is linked to poorer health and less social and political participation (OECD, 2013b). There is, for these reasons, a significant interest in information about effective interventions to increase academic achievement and enhance educational prospects. The review we plan to conduct will focus on service learning in primary and secondary education. Service Learning is curriculum-based community service that integrates classroom instruction with community service activities. The connection with specific courses and having clearly stated learning objectives is what distinguishes service learning from other forms of volunteer work. Service learning should "address real community needs in a sustained manner over a period of time; and assist students in drawing lessons from the service through regularly scheduled, organised reflection of critical analysis activities, such as classroom discussions, presentations, or directed writing" (Pritchard, 2002, p. 20). Well-designed service-learning activities can deepen learning and foster higher-order thinking skills by providing students with opportunities to apply their learning to a challenging situation or problem in their community. The development of service learning as a pedagogical method that integrates community service into the course curriculum began in the 1970s, primarily in the United States (Spring et al., 2008). In the nineties, service learning became institutionalised in public education in the United States (Peterson & Seligman, 2004). In 1990 in United States, the National and Community Service Act created Serve America (later named Learn and Serve America), which was a federal programme dedicated to providing grants and other supports for service learning activities in schools and community-based organisations. Further, in 1994, service learning became a recognised method for meeting the aims of federal school funding (included in the Elementary and Secondary Education Act). In addition to these federal policies, several states and school districts mandated the incorporation of service learning into the course curriculum (Spring et al., 2008). Service learning is not yet as widespread in the rest of the world. However, the OECD-project "Innovative Learning Environments" mentions service learning as a pedagogical method to put learners at the centre (the first of the seven principles of learning needed to redesign the learning environments to meet the challenges of the 21st century) (Dumont et al., 2010). According to Furco (2010) "service-learning is one of the fastest growing educational initiatives in contemporary primary, secondary and post-secondary education" (Furco, 2010, p. 228). Outside of the United States, service-learning initiatives are part of the education systems of Argentina, Columbia and Singapore (Chua, 2010; Ierullo, 2016; Perold & Tapia, 2008). Argentina hosts the Latin American Center for Service-Learning (CLAYSS) which was created in 2002 to support students, educators and community organisations in the development of service-learning projects in Latin America. Service learning is not part of any educational policy in Europe although the EU recognises service learning as a way of achieving citizenship education (European Commission/EACEA/Eurydice, 2017). Service learning is however emerging in many European countries including Germany, Ireland, Italy, Spain and the United Kingdom (Furco, 2010) and currently CLAYSS is assisting in the creation of the Central and Eastern European Service-Learning Network (Regina & Ferrara, 2017). In several European nations there are organisations (nonprofit community-based) with programmes dedicated to providing supports for service learning activities in schools (Luna, 2012): Lernen durch Engagement in Germany, Center for Frivilligt Socialt Arbejde in Denmark, Lernen durch Engagement in Switzerland, Noi-orizonturi in Romania, MOVISIE in the Netherlands and Fundación Tomillo in Spain. School-based service-learning is a teaching strategy that explicitly links community service to academic instruction (Billig, 2000). In the United States, "service-learning" is an official term used by policy makers and educational leaders. Service-learning is distinctive from traditional voluntarism or community service in that it intentionally connects service activities with curriculum concepts and includes structured time for reflection. Service-learning is not an add-on to an existing curriculum, a requirement of a minimum hours of service to graduate or service assigned as punishment. Rather, students are required to use academic knowledge and skills to address genuine community needs. A clarifying example is given by the National Youth Leadership Council (https://www.nylc.org/page/our-philosophy): "Picking up trash on a river bank is service. Studying water samples under a microscope is learning. When science students collect and analyze water samples, document their results and present findings to a local pollution control agency—that is service-learning". Service learning programmes can take many forms and are very diverse in content. However, a common set of elements are critical for a success full implementation of service learning. The National Youth Leadership Council and RMC Research Associates have developed a set of eight quality service-learning standards (the K-12 Service-Learning Standards for Quality Practice) with input from youth, teachers, administrators, youth agencies, policymakers, community members and other stakeholders. The standards are: Meaningful service: Service-learning actively engages participants in meaningful and personally relevant service activities. Link to curriculum: Service-learning is intentionally used as an instructional strategy to meet learning goals and/or content standards. Reflection: Service-learning incorporates multiple challenging reflection activities that are ongoing and that prompt deep thinking and analysis about oneself and one's relationship to society. Diversity: Service-learning promotes understanding of diversity and mutual respect among all participants. Youth voice: Service-learning provides youth with a strong voice in planning, implementing and evaluating service-learning experiences with guidance from adults. Partnerships: Service-learning partnerships are collaborative, mutually beneficial and address community needs. Progress monitoring: Service-learning engages participants in an ongoing process to assess the quality of implementation and progress toward meeting specified goals and uses results for improvement and sustainability. Duration and intensity: Service-learning has sufficient duration and intensity to address community needs and meet specified outcomes. The complete document can accessed at https://www.nylc.org/page/standards. Research shows that the students who participate in service learning may benefit both personally, socially and academically (e.g., Celio et al., 2011; RMC Research Corporation, 2002). Service learning, by connecting education to real world issues and allowing students to address problems they identify, may be particularly efficacious as it increases engagement and motivates students, in particular students who might not respond well to more traditional teaching methods (see, e.g., Bridgeland et al., 2008; Kraft & Wheeler, 2003; Scales & Roehlkepartain, 2005). Motivation for learning and school engagement play a critical role in students' academic success (e.g., Fan & Wolters, 2014; Skaalvik & Valas, 1999). Motivated students tend to do better at school. According to OECD, students who are among the most motivated score the equivalent of more than one school year higher in PISA than the least-motivated students and motivation is further positively related to life satisfaction (OECD, 2017b). Theoretically, Kolb's (1984) model of experiential learning is often referred to as the foundation for understanding how service-learning might work. Experiential learning theory defines learning as "The process whereby knowledge is created through the transformation of experience" and knowledge is defined as: "a transformation process being continuously created and recreated, not an independent entity to be acquired or transmitted" (Kolb, 1984, p. 38). Kolb further suggests that experiential approaches to learning such as service-learning are better at accommodating learners with different learning styles than traditional didactic approaches such as classroom-based teaching. Experiential learning is inspired by pragmatist philosopher John Dewey's six-step process of experiential logical inquiry. According to Dewey the six steps are: (1) encountering a problem, (2) formulating a problem or question to be resolved, (3) gathering information which suggests solutions, (4) making hypotheses, (5) testing hypotheses and (6) making warranted assertions (Dewey, 1938; Giles & Eyler, 1994; Kolb,1984). Kolb's (1984) model comprises these steps into a four stage experiential learning cycle involving: Concrete Experiences, Reflective Observation, Abstract Conceptualisation and Active Experimentation (Cone & Harris, 1996; Kolb, 1984). Based on this conception, students participating in service-learning are engaged in a cycle in which their work in the community promotes written and/or oral reflection. Under the guidance of teachers or instructors, reflective work may be used to form abstract concepts and generate hypotheses, which may then be cycled back into further concrete experiences. According to Kolb this way of learning allows a variety of students with different learning styles and abilities to develop and integrate their skills (Cone & Harris, 1996). Service-learning provides an opportunity for students to move between perceiving new information through experiencing the concrete, tangible, felt qualities of the world within the community and taking hold of new information through abstract conceptualisation, thinking and analyzing. The pattern in which a learner moves between these levels of experience are thought to reflect an individual learning style, and service-learning is thought to allow each student to move between the levels in a way consistent with their own learning style (Kolb et al., 2002). Another strand of theory which offers a potential understanding of the theory of change behind service-learning is Situated Learning. The term "situated learning" refers to learning that occurs within a particular and authentic context through the individual's social participation. Rather than focusing on learning as a primarily cognitive process involving a number of tasks, situated learning theorists study the process in which individuals become new members of a learning community. According to the theory newcomers within a learning community move from a state of legitimate peripheral participation to full participation through a process that involves continuous negotiation, collaboration and reflection (Wolfson & Willinsky, 1998). In their often cited work: "Situated Learning: Legitimate Peripheral Participation", Lave and Wenger (1991) focus on acquisition of skills and knowledge that takes place outside of traditional schooling within communities of practice. Based on an ethnographic investigation of traditional and nontraditional apprenticeships in Mexico, Liberia and the United States, Lave and Wenger propose that learning should not be viewed as the mere transmission of knowledge but as a distinctly embedded and active process. Learning is thus perceived as a contextualised process in which content is learned through doing activities. Furthermore, Lave and Wenger suggest that motivation too is "situated", as learners are naturally motivated by their growing value of participation (Lave & Wenger, 1991). Based on this approach students participating in service-learning inherently become motivated to learn as this enables them to move from being novices to becoming full participants within the learning community. Furthermore, students participating in service-learning may become motivated as they experience how their own participation increases in value as they progress from being newcomers towards the centre of the community of practice. In situated learning the construction of meaning is seen as being tied to specific contexts and purposes. For students participating in service-learning this may be particularly important, as service learning may enable them to socially construct meaning which makes learning matter beyond school. Two systematic reviews with meta-analyses are found in Conway et al. (2009) and Celio et al. (2011), both performing searches up to spring 2008. The review by Conway et al. (2009) analysed four outcomes: academic, personal, social and citizenship outcomes. They included studies of community service or volunteerism as well as service learning without distinguishing between these very different types of interventions (except in a moderator analysis), participants were not limited to primary and secondary education (although all results were shown separately for grade kindergarten to 12 students but without distinguishing between community service or volunteerism and service learning) and many of the included studies did not have control groups. The review by Celio et al. (2011) required included studies to analyse service learning using a control group but participants were not limited to primary and secondary education. Five outcome areas were analysed: attitudes toward self, attitudes toward school and learning, civic engagement, social skills and academic achievement. Separate results for primary and secondary education (grades kindergarten to 12) was only shown for the overall effect, that is, the mean of the five outcomes attitudes toward self, attitudes toward school and learning, civic engagement, social skills and academic achievement. The analysis of primary and secondary education outcomes did not take into consideration that more than one outcome per study was included in the meta-analysis (i.e., they did not take into account the dependencies between the effect sizes). Besides being up to date, the major differences between these two systematic reviews and the current proposal are that we will focus on service learning for primary and secondary education, only include studies with a control group, all relevant outcomes areas will be analysed separately and we will take into consideration the dependencies between effect sizes. In addition, there are several literature reviews of studies conducted in the United States (Billig, 2000, 2002, 2003, 2004). None of them is a systematic review and no data synthesis is performed in any of them. The review we plan to do differs in substantial ways from these existing reviews. It is systematic and a meta-analysis will be conducted. The main objective of this review is to answer the following research question: What are the effects of service learning on academic success, NEET status, personal and social skills and risk behaviour of students in primary and secondary education (grades kindergarten to 12)? Further, we will investigate the following factors with the aim of explaining potential observed heterogeneity: study-level summaries of participant characteristics (e.g., studies considering a specific gender, age or socioeconomic level or studies where separate effects for girls/boys, primary school/secondary school or low/high socioeconomic status are available) and quality of the service learning programme according to the standards as outlined in section The intervention. The moderator analysis will be performed as outlined in section Moderator analysis and investigation of heterogeneity. The proposed project will follow standard procedures for conducting systematic reviews using meta-analysis techniques. Randomised controlled trials will be included. In order to summarise what is known about the possible causal effects of service learning, we will include all study designs that use a control group, that is, a group of students not participating in service learning. The control group may be offered treatment as usual or an alternative treatment. The study designs we will include in the review are: Randomised and quasi-randomised controlled trials (allocated at either the individual level or cluster level, e.g., class/school/geographical area etc.). Nonrandomised studies (service learning has occurred in the course of usual decisions, the allocation to service learning and no service learning is not controlled by the researcher, and there is a comparison of two or more groups of participants, i.e., at least a treated group and a control group). Studies using single group pre-post comparisons will not be included. Nonrandomised studies using an instrumental variable approach will not be included—see the Appendix (Justification of exclusion of studies using an instrumental variable (IV) approach) for our rationale for excluding studies of these designs. A further requirement to all types of studies (randomised as well as nonrandomised) is that they are able to an Studies for example, the treatment is given to teachers in one school only and the comparison group is teachers at school more schools for that separate the treatment effect from the school Even within of teachers in may mean that have to be at the level to be able to a situation of not being able to separate treatment effect from The review will include in primary and secondary education (grades kindergarten to 12) in education. The included to primary and secondary defined as the first two steps in a educational of primary education, secondary education and tertiary or higher education. The number of years a primary schooling across the OECD countries, though most often primary schooling is or after which secondary education (e.g., in the form of The is the for in and most of and the is the for school systems in countries such as Italy, and The age included will between countries, and between states within from to In some countries, kindergarten can however to programmes outside of primary school and include to years. Service learning such will be that is, kindergarten be a part of primary school for a study to be included. to secondary defined as the in a educational The number of years a secondary schooling across the OECD countries, though most often secondary schooling is or The is the for in and most of and the is the for school systems in countries such as Italy, and The age included will between countries, and between states within will from to Studies that meet will be from all will in school and in Service Learning is a curriculum-based community service that integrates classroom instruction as classroom discussions, presentations, or directed with community service activities. Service learning may be or and should have service activities that take place outside of the It should take place in the community including the school as part of the community. Service learning is organised in to an academic course or curriculum and has clearly stated learning Service learning should address real community needs and students in drawing lessons from the service through regularly scheduled, organised reflection or critical Community service or activities that do not integrate classroom instruction will be The primary focus is on of academic success and NEET status employed nor in education or training compulsory The primary outcomes are: on students' achievement tests education, training on students' achievement only will be that is, tests (e.g., and tests (e.g., of tests (e.g., National Assessment of and of academic (e.g., of we do not to studies follow up outcomes in the compulsory NEET status is included as a primary A secondary focus is on of personal and social skills and attitudes towards and risk behaviour as and risk by or by personal and social only and reliable outcomes that have on a different population is i.e., not will be included. of outcomes are from the Skills & or the of the the Skills Scales & and the Scales & 1999). Studies will only be included they at least one of the primary or secondary outcomes. it is not from the of outcome in the studies they are we will use to a is or will not where have a of from a It will be any potential effects have in any included Duration of for will year follow up year follow up than year follow up of The of the is primary and secondary education (grades kindergarten to 12) in public or will be studies will be through searches in literature and in specific to and will be Center example of the strategy used for the on the is The will be to the and of the different literature literature will be & National Research Education Commission of the National Youth Leadership Research American for Center for and Research on Learning and of literature might be the process. specific will be International for Research on Service-Learning and Education of Experiential Education of of of and in the Community in Service-Learning Research The International of Research on Service-Learning and Community Engagement In order to both studies and literature we will primary strategy will be to related and The review will also of included primary studies for new with will to and ongoing Randomised controlled trials are but we that a of studies will be conducted without of participants. Studies of the effect of service learning are required to have a control group for in the may be for example, time policy or participant They all group or of on risk and participant The will be according to the risk of model outlined in section of risk of in included The risk of makes it possible to between studies with of Studies that have with a risk of will not be included in the data example of a study that may be included is et al. in which students at one school were assigned by classroom to either a for classroom curriculum or a for service learning Another Scales et al. assigned students in schools to where after schools which of their be service-learning and which be control A of analysis of were conducted to service-learning students with control students with on the as the A

A multicenter ambispective study using the Canadian Spine Outcomes and Research Network to compare clinical outcomes in adult patients with isthmic spondylolisthesis who received surgery. The purpose of this study is to compare 1-year postoperative clinical outcomes between posterior instrumented fusion with and without interbody fusion in patients with isthmic spondylolisthesis. Despite the increased use of interbody fusion in patients with isthmic spondylolisthesis, clinical superiority has not been demonstrated. It remains unclear what the optimal surgical approach is for this population. The primary outcome was changed in leg pain at 1 year. Secondary outcomes were changed in Oswestry Disability Index, Short Form-12 Physical Component Score, and back pain at 1-year postoperative follow-up, estimated intraoperative blood loss, length of surgery, length of stay, number of transfusions, and adverse events. Descriptive statistics, Student t test, χ2 test, and stepwise multivariable regression were used for analysis. In total, 300 patients were included in this study. Of the 300 patients, 252 received posterolateral instrumented fusion with interbody fusion and 48 received posterolateral instrumented fusion alone. There were no significant differences in primary and secondary clinical outcomes at 1-year postoperative follow-up between the 2 groups. There were no significant differences in estimated blood loss (441 vs. 356 mL), length of surgery (210 vs. 224 min), length of stay (4 vs. 4 d), rate of transfusions (5.6% vs. 8.3%), and number of adverse events (33% vs. 23%) between patients who received interbody fusion and patients who did not. The addition of interbody fusion was not a significant variable for primary and secondary clinical outcomes in the stepwise multivariable regression analysis. There were no significant differences in clinical outcomes at 1 year or in the number of early complications between patients who received posterolateral fusion or posterior/transformational lumbar interbody fusion. Level III.