The increasing studies have been conducted using whole genome DNA methylation detection as one of the most important part of epigenetics research to find the significant relationships among DNA methylation and several typical diseases, such as cancers and diabetes. In many of those studies, mapping the bisulfite treated sequence to the whole genome has been the main method to study DNA cytosine methylation. However, today’s relative tools almost suffer from inaccuracies and time-consuming problems.In our study, we designed a new DNA methylation prediction tool (“Hint-Hunt”) to solve the problem. By having an optimal complex alignment computation and Smith-Waterman matrix dynamic programming, Hint-Hunt could analyze and predict the DNA methylation status. But when Hint-Hunt tried to predict DNA methylation status with large-scale dataset, there are still slow speed and low temporal-spatial efficiency problems. In order to solve the problems of Smith-Waterman dynamic programming and low temporal-spatial efficiency, we further design a deep parallelized whole genome DNA methylation detection tool (“P-Hint-Hunt”) on Tianhe-2 (TH-2) supercomputer.To the best of our knowledge, P-Hint-Hunt is the first parallel DNA methylation detection tool with a high speed-up to process large-scale dataset, and could run both on CPU and Intel Xeon Phi coprocessors. Moreover, we deploy and evaluate Hint-Hunt and P-Hint-Hunt on TH-2 supercomputer in different scales. The experimental results illuminate our tools eliminate the deviation caused by bisulfite treatment in mapping procedure and the multi-level parallel program yields a 48 times speed-up with 64 threads. P-Hint-Hunt gain a deep acceleration on CPU and Intel Xeon Phi heterogeneous platform, which gives full play of the advantages of multi-cores (CPU) and many-cores (Phi). Epigenetics focus on the problem that why lives with same DNA sequences have different characters. Epigenetics is an important part of the genetics. There are two kinds of information in the genome: the explicit information in DNA sequence and implicit information hiding in the combination of bases. These implicit information control some characters of lives . AlthougWhole genome DNA methylation detection is one of the most important part of epigenetics research. It is supposed to have a great effect on cancers and tumors, and even be involved in the senility of human. In addition, it is believed that in medical aspects, DNA methylation may have a strong relationship with diabetes and immunological diseases –6. EspecFor example, BSMAP  is a repNowadays, there are mainly two parts of DNA methylation detection: biological sequencing by experiment and computer simulation. After the biological experiment, we can acquire the sequences with assistant location information. The samples of paired-ends sequences information are shown in Fig. According to the location information in the last three columns, we could acquire the mapping range to narrow the suspected area, as well as avoiding the cost of aimless mapping.After locating specific areas of mapping in the reference sequence, we use the Smith-Waterman algorithm  to map tIn our work, we use the sequences of one end with bisulfite treatment and another end without bisulfite treatment, which is a relatively newer and harder area may lead to better results, to solve the problem of inaccuracy. First, we use OpenMP to design a fine-grained multi-threads approach to massively parallelize the complex tasks of big data to achieve a good performance. Then, we propose a new parallel Smith-Waterman algorithm to map the sequence precisely in the range of 1000 bp around the preliminary location. The new algorithm we proposed is removing whole backtracking step of original Smith-Waterman method by sacrificing a small amount of space effectiveness to in exchange for higher performance gains. Specifically, we record the best source direction for each matrix element in the matrix score calculation step. Based on this information, we can backtrack directly without the need for redundant branch judgments. This is a more efficient method of determining the best matching position.After the data screening and deletion of PCR duplicates, we choose the best mapping result for DNA methylation analysis. In order to promote the performance, we design a centralized looping IO mode and build an index of input data to effectively avoid the extra overhead caused by frequent IO operation. Further, we develop the program to exploit multi-level parallelism using multi-threads and multi-processes, which could be adjusted flexibly according to various computing platform. And the Intel Xeon Phi coprocessors are also used to cooperate with CPUs to achieve a faster computing speed. At last, we evaluate our method on Tianhe-2 supercomputer. The results show that the correctness of program is guaranteed both for serial version and parallel version. The speed-up is 47 times with 64 threads, and the speed-up of multiple nodes is nearly linear.After the authentication, we find that Hint-Hunt could figure out the methylated information accurately based on the mapping in a specific area, but when facing the computation of big data like the whole human genome, there are still problems like too much time consumption, especially when we use the sequence data with more cover layers to reach a large scale. In order to solve these problems, we design the parallel version of Hint-Hunt, the P-Hint-Hunt, to optimize the partition of task, the establishment of index and the function of IO with multi-levels parallelism.Because of the massive data, nearly 3 TB, the serial program could not meet the requirements of running time. Therefore, we optimize the serial program to the parallel version and implement the use of multi-threads based on OpenMP, reaching a speed up of 47 times using 64 threads.There are two alternatives to implement multi-threads: the coarse parallelism of chromosome level and the fine-grained parallelism of target sequence level. The coarse parallelism means we could use one thread to process the data from each chromosome, 25 threads in total. This approach is easier to implement as there is no need to consider the task division. But because of the difference of the amount of target sequences located on the same chromosome, there will be huge difference of loads on different threads, which will lead to severe load imbalance among these threads. On the contrary, the fine-grained parallelism version could modify the number of threads dynamically according to the amount of data, and reach the load balance to the maximum extent.Before we start, we analyze the data dependency and program structure. The only dependency of the data to be processed is that target sequences with the same ID must be processed within the same thread to pick out the best result. Except this, there is no any other data dependence among the target sequences. The analysis of the program structure divide the program to two main parts: the I/O part and the process of characters. The second part takes the most of running time, which is needed to be parallelized eagerly.The implementation consists of three main parts. (1) Loading data and pre-classification. According to the input data, with an order of ID number, we classify all of the input data to avoid the bad influence caused by data dependence. We set the same ID number for target sequences, and divide the indexes to different threads equally basing on the amount of target sequences in each index. This procedure insures the correctness of the program and keeps the load balance, which also reduces the running time. (2) Concentrated loop IO operation help to control the usage of memory. In the serial program, the program firstly reads the target sequence file line by line and then computes and processes. After these process operations, the program writes the result back to result arrays and finally writes the results back to result files when all the processes are over. The multi-threads structure needs to import the data into memory first to help task partition and establishment of indexes, but the frequent IO operations are barriers for pipeline execution on hardware. So we use concentrated loop IO operation (import two million lines of sequence data once upon a time) to avoid the performance decrease caused by frequent IO operation and help control the usage of memory at the same time. (3) The safety of multi-thread running. In the programming of multi-thread program, there are both shared space and private space in every thread, so first we have to classify the shared parameters and the private parameters. In the program, the array of reference sequence and the array of overall methylated position are shared by all the threads. In addition, to make sure the safety of multi-thread running, we use the thread-safe functions instead of the general function. Take the function in C++ base for example, “strtok” is not thread-safe, which means it may occur errors when running several threads sharing memory. So we use the function “strtok_r” instead.Using the multi-cores on single node could not meet the requirement of time consumption when the data scale big enough. To make full use of the structure of supercomputer, the multi-processes version of program could take the advantages of multiple computing nodes to accelerate the running time extremely.First, the program calculates the amount of data needed to be divided to each process according to the number of processes. During the division of tasks, we need to insure that target sequences with exactly the same ID number must be divided to the same process. The processes communicate with each other to acquire the start and end position of their tasks, and then start to process data, where the load balance have been insured among all processes.Nowadays, more and more supercomputers provide powerful computing capacities base on a heterogeneous architecture. Intel Xeon Phi coprocessor and GPUs are added to the traditional computer architecture to seek for an increase of computing scale, and the former is more powerful in parallel computing and scientific computing. Take the Tianhe-2 super computer for an example, each of its computing nodes have two Xeon E5 2692 processors and three Intel Xeon Phi coprocessors. So we optimize the parallel program especially for the architecture of super computers.The main challenge of programming on coprocessors is the usage of memory on coprocessors. Because the coprocessors cannot access to the main memory as CPU does, so the memory remains to be idle on each coprocessor in practical is nearly 6GB. However, the memory allocating on CPUs is about 28GB. Therefore, we use CPU to control the data transformation between main memory and memory on coprocessors. We use 112 threads of 56 cores on the Intel Xeon Phi coprocessors to process 100 million lines  of target sequences each time, and then carry out data transformation between these two kinds of memory.About the cooperation of Intel Xeon Phi coprocessor and Intel CPU, we find that the computing capability of three coprocessors using 56 cores each is nearly the same as two CPUs with 12 cores each after the tests. So, we divide the target sequence file into 12 parts and distribute two parts of them to each coprocessor and three parts of them to each CPU processor. The dynamic distribution of tasks makes sure the load balance between CPUs and coprocessors and makes the full use of all the computing resources.The reference sequences are stored in the file in the format of 50 bp per line, which is imported line by line. Therefore, when the input data become large, the time of IO could be very substantial. In order to solve this problem, we use a pre-process of reference sequence file to remove the line break symbols in it and make sure the location of each base remain the same. After this operation, the program could import the reference sequence file in a very short time. It only takes 20–30 s rather than original several hours.At the very beginning of our program, in order to record the methylated or non-methylated information, we use structural arrays to record the start and end mapping position, score, etc. Take one of several input files for example, there are 9,242,825 lines of sequence in the target sequence file, and every one of the sequences needs the space of 212 Bytes. That makes the total space needed for the target sequences to be used as a buffer are 212B × 9242825 = 1.825 GB. In addition, another 3GB are still necessary to store the human genome reference sequences because the length of reference is 3G. In order to store the methylated and non-methylated information of each base in the references, we need extra 3G × 8B = 24GB memory space. While, the target sequence file in this example is the minimum one, which means that there could be a need for 70 × 1.825GB + 3GB + 24GB = 154.75 GB memory space for the largest target sequence file consisting 650 million lines of sequences, nearly 70 times bigger than the first example. The demand for memory is obviously beyond the capability of common computing station, and will keep increasing as the target sequence file increases.Aiming at solving these problems, we optimize the data structure to minimize the memory allocation. When storing the information of methylated and non-methylated, the program uses a buffer in each thread, which is allocated temporarily, rather than a permanent piece of block in the memory. And each thread then releases the buffer after a group of sequences (sequences with the same ID are treated as one group) is processed, and transfers the results in the buffer into the overall array. Using the strategy above, which we call it “write through”, we could write back the methylated or non-methylated information back to the overall array and control the usage of memory effectively at the same time. In the end, the overall memory allocating of our program is about: 3GB + 24GB + 1GB = 28 GB (the extra 1 GB is from other static parameters), which is acceptable in general computing platform and proved to be an effective way to optimize the memory allocation.The basic environment of the computing platform is shown in Table The test consists three main parts: the correctness, the speed-up of parallelism and the scale-up of parallelism.About the correctness of our program, we checked the results of the test samples by manual work, the results showed complete agreement with the expected results, which means the program could give out the correct results for the given target sequences.As to tests of speedup, we used the dataset consists of 10,000 lines, 100,000 lines, 1 million lines, 3 million lines and 9 million lines. And we used 6 kinds of different numbers of threads to carry out overall tests. The results of test for 9 million lines of target sequences are shown in Table When processing the same amount of data, the serial version of program uses 86062 s. From the comparison between the serial program and the parallel program we can know that our work can achieve a high speedup.At last, we used 10 million, 50 million and 110 million lines of target sequences to test whether the program will be stable when facing big data to evaluated its scale-up. And the results of these test show the multi-threads program could run normally and keep efficient for big data.As to the tests for multi-processes program, we used sample 1 and sample 2, whose amount of data are 9 million lines (1087 MB) and 48.492 million lines 59630 MB) respectively. The test results are shown in Table 0 MB respFrom the lists, we could tell that the program using multi-processes on multiple computing nodes has an obvious speed-up compared to multi-threads only.The test computing environment is similar with what we used above, except extra three Intel Xeon Phi coprocessors with 57 cores each. The frequency of every one of these cores is 1.1 GHz. And one of the 57 cores is used as a managing core, so we could use the rest 56 cores.During the test, we opened two threads on each core, and 112 threads total on each coprocessor. The sample 1 and sample 2 are still 9 million lines and 48.492 lines, respectively. The testing results are shown in Table From the results, we could figure out that the computing capacity of the whole three coprocessors is about 1.2 times promotion comparing with two CPUs.Aiming at a classic problem in epigenetics: the prediction of DNA methylation status, we proposed and implemented a computing tool, and parallelized it with multi-threads and multi-processes. The parallel version with a high speed-up could run both on CPU and Intel Xeon Phi coprocessors. In the program, we implement the prediction of DNA methylation status, threshold filtering, score sharing and result data integration. The pre-process of reference sequence file and concentrated loop IO operation keep the program correct and running in a load balanced and memory efficient way.In the evaluation part, we evaluate the program about its correctness, its speed-up and scale-up, and analyzed the effectiveness of parallelism. The results of these tests show that the correctness of program is guaranteed both for serial version and parallel version. When we use multiple threads, the speed-up is 47 times with 64 threads, and the speed-up of multiple nodes is nearly linear. Further, we can see that multi-processes on multiple computing nodes, which can be applied to larger dataset, has an obvious speed-up compared to multi-threads only. And the Intel Xeon Phi coprocessors are also used to cooperate with CPUs to achieve a faster computing speed. In general, after parallelism of the program, the running time decreases sharply and the computation resources are fully used.So far, the program has been paralleled on different levels, taking full use of CPU and Intel Xeon Phi coprocessors on super computer. But as a very important part of the whole pipeline, the program needs data from the upstream. So in the future, we are supposed to combine the whole pipeline of analyzing DNA methylation into one single parallel program to create a seamless tool to analyze DNA methylation.


The evaluation of educational programs has become an expected part of medical education. At some point, all medical educators will need to critically evaluate the programs that they deliver. However, the evaluation of educational programs requires a very different skillset than teaching. In this article, we aim to identify and summarize key papers that would be helpful for faculty members interested in exploring program evaluation.In November of 2016, the 2015-2016 Academic life in emergency medicine (ALiEM) Faculty Incubator program highlighted key papers in a discussion of program evaluation. This list of papers was augmented with suggestions by guest experts and by an open call on Twitter. This resulted in a list of 30 papers on program evaluation. Our authorship group then engaged in a process akin to a Delphi study to build consensus on the most important papers about program evaluation for medical education faculty.We present our group’s top five most highly rated papers on program evaluation. We also summarize these papers with respect to their relevance to junior medical education faculty members and faculty developers.Program evaluation is challenging. The described papers will be informative for junior faculty members as they aim to design literature-informed evaluations for their educational programs. Medical educators spend much of their time developing and delivering educational programs. Programs can include didactic lectures, online modules, boot camps, and simulation sessions. Program evaluation is essential to determine the value of the teaching that is provided -2, whethProgram evaluation can be mistaken for assessment or research, but these constructs are subtly different. Within medical education, assessment is generally understood to be the measurement of individual student performance . While sIn 2016, the Faculty Incubator was created by the Academic Life in Emergency Medicine (ALiEM) team to create a virtual community of practice (CoP) -6 for eaThis paper is a narrative review, which highlights the literature that was felt to be the most important for faculty developers and junior educators who wish to learn more about program evaluation.During November 1-30, 2016, the junior faculty educators and mentors of the ALiEM Faculty Incubator  discusseThis list was expanded using two other methods: articles recommended during a YouTube Live discussion featuring mentors with significant experience in program evaluation  and a call for important program evaluation papers on Twitter. We ‘tweeted’ requests to have participants of the free open access meducation and medical education (#FOAMed and #MedEd) online virtual communities of practice  provide The importance of these papers for program evaluation was evaluated through a three-round voting process inspired by the Delphi methodology -11. All Western Journal of Emergency Medicine and Population Health [Similar methods were used by the ALiEM faculty incubator in a previous series of papers published in the n Health -15. Readn Health  because The ALiEM faculty incubator discussions, expert recommendations, and social media requests yielded 30 articles. The paper evaluation process resulted in a rank-order listing of these papers in order of perceived relevance as indicated by the results of round three. The top five papers are expanded upon below. The ratings of all 30 papers and their full citations are listed in Table .The following is the list of papers that our group has determined to be of interest and relevance to junior faculty members and faculty development officers. The accompanying commentaries are meant to explain the relevance of these papers to junior faculty members and also highlight considerations for senior faculty members when using these works for faculty development workshops or sessions.1. The Association for Medical Education in Europe (AMEE) Education Guide no. 29 Evaluating Educational Programmes : This education guide within medical teacher begins with a brief discussion of the history of program evaluation. It goes on to recommend a framework of evaluation for educators that focuses on the methodology of evaluation, the context of evaluation practice, and the challenge of modifying existing programs with the results the evaluation. This overview includes detailed sets of questions for evaluators to ask about programs that they review. Perhaps the most salient piece of advice from this paper is that improvement even when modesty is valuable.Relevance to Junior Faculty MemberThis is a high-yield read for the junior faculty educator because it provides a succinct and comprehensive overview of program evaluation through the presentation of a framework, which can be adapted by junior faculty educators. Each step within the framework is accompanied by an explanation to assist the reader in understanding the components.Considerations for Faculty DevelopersFaculty developers should be expected to understand program evaluation in the context of its history. This manuscript summarizes the historical program evaluation literature from within and beyond medical education in a way that contextualizes modern controversies and informs current approaches. Faculty developers should use this manuscript to center themselves within the literature. The framework provided may also guide their approach to evaluating the programs of their more junior faculty members.2. Program Evaluation Models and Related Theories- AMEE Guide No. 67 : This guide discusses the three main education theories that underlie various evaluation models . It begins by describing the purpose of program evaluation, clarifying the definition of program evaluation, and explaining why we evaluate educational programs. The authors conclude that the main purpose of any educational program is change – be it intended or unintended – and defines program evaluation as the “systematic collection and analysis of information related to the design, implementation, and outcomes of a program for the purpose of monitoring and improving the quality and effectiveness of the program.” The guide ends with a description of four evaluation models  informed by these education theories.Relevance to Junior Faculty MembersChange is the most important aspect of any educational program, so measuring change should be the focus of a program evaluation. It is important for junior educators to understand that evaluation should analyze both the intended and unintended change resulting from a program, rather than solely investigating the intended outcomes. By discussing several different evaluation models and their underlying educational theories, this guide will allow the junior faculty educators to choose the best evaluation modality that is most relevant to their individual educational activity.Considerations for Faculty DevelopersThis paper may enhance a faculty developer’s foundational knowledge of program evaluation by summarizing its underlying education theories and common models. It may also serve as a frequent reference for faculty developers as they select conceptual frameworks to inform the evaluation of educational programs.3. Twelve Tips For Evaluating Educational Programs : The tips provided in this article can be summarized into three primary themes. Prior to beginning the evaluation, it is important to understand the program, be realistic in what is possible, define the stakeholders, determine the intended outcomes of the program, select an evaluation paradigm, and choose a measurement modality. As evaluation design begins, assemble a group of collaborators who will help to brainstorm, guide the methods used and assist in the piloting of the evaluation. Finally, they recommend avoiding common pitfalls such as confusing program evaluation with learner assessment, evaluating an outcome that is not consistent with the program’s goals, using an unreliable instrument or an instrument without context-specific validity evidence and having unrealistic expectations.Relevance to Junior Faculty MembersPlanning for program evaluation must take place as part of the program design process and not as an afterthought. The 12 tips provide salient advice and a model that is thorough, yet easily achievable for junior faculty educators. While the format of this paper presents only an overview of several complex concepts , the author provides references for a more in-depth review of these topics.Considerations for Faculty DevelopersFaculty developers will find this concise and clear paper, helpful as both a reference for mentees and to further their own understanding of program evaluation. In addition to foundational tips, the author summarizes advanced concepts that may apply to a faculty developer’s educational practice. Rather than simply presenting a formula for program evaluation, the inclusion of the strengths and weaknesses of various paradigms allows a more nuanced understanding of the gray areas in evaluating educational programs. Referencing the complexities of validity evidence and the potential drawbacks of a patient-related outcome approaches may spark dialogue in faculty development programs and collaborations. Finally, the references included are thoughtful and relevant and would be good additions to faculty developers’ personal libraries.4. Rethinking Programme Evaluation in Health Professions Education-Beyond 'Did it Work?' : This article begins with a provocative analysis of Kirkpatrick hierarchy, establishing the multiple problems that arise when evaluation programs focus solely on outcomes. Beyond the outcome ("Did it work?"), it reinforces the importance of considering the educational theory ("Why will it work?"), the process ("How did it work?"), the context ("What context is the program operating in?”), and unexpected results within the evaluation of a program. In doing so, the authors open the discussion regarding which evaluation approaches might be better suited for different educational programs. More important than finding "the perfect" evaluation model is gaining a holistic view of a program that clarifies the relationship between interventions and their outcomes.Relevance to Junior Faculty MembersThe spirit of this paper is laudable: do not aim to find a single explanation or theory, but familiarize yourself with the literature and determine the best way to evaluate a program within your own context. It will guide junior faculty in their efforts to develop new educational programs within their educational contexts; focusing not only on if a certain program works, but on why it should work, how it worked, and what else occurred. These questions will guide implementation processes and inform future approaches.Considerations for Faculty DevelopersProviding a historical and theoretical overview of program evaluation as a discipline, this article traces the roots of program evaluation. It highlights the importance of going beyond the Kirkpatrick hierarchy to develop a greater understanding of why a program might succeed or fail. The first figure clearly outlines essential elements that explain how theory intersects with implementation and evaluation and is a must read for those who are training program evaluator to their faculty members, to guide them towards richer methods for describing curricula or programs in their scholarly work. Notably, this advice was considered controversial and should be carefully considered .5. Perspective: Reconsidering the Focus on "Outcomes Research" in Medical Education- a Cautionary Note : There is an increasing emphasis on higher-level outcomes (e.g. patient outcomes) in educational research which presents challenges to researchers. After discussing the limitations of this approach, the authors offer salient advice for educational research: begin with a study question and proceed in a stepwise fashion to determine the intended outcome and measurement tool, rather than beginning with the measurement tool and working backward. They recommend beginning with Kirkpatrick level one outcomes (e.g. reaction) and sequentially progressing to higher levels  [results)  throughoRelevance to Junior Faculty MembersThere are several challenges and pitfalls associated with developing medical education studies and evaluating patient-level outcomes. While patient-level outcomes will have a role as educational research continues to evolve, they can be difficult to fund without large grants as multi-site involvement is required to obtain adequate power. Lower level outcomes, such as student learning or behavior, remain important for assessments of novel interventions, as well as for isolating the most effective components of an intervention. This is important advice for junior faculty members who are already influenced by the focus on patient-level outcomes within medical research.Considerations for Faculty DevelopersFaculty developers must acknowledge the problems inherent to seeking patient-level outcomes in educational research and program evaluation. Junior faculty members may be inclined to “shoot for the moon” and seek an impact on patient outcomes before first establishing that their program is well received, leads to attitude and behavioral change, and is sustainable.As with our previous papers -15, thisWe present five key papers addressing the topic of program evaluation with discussions and applications for junior faculty members and those leading faculty development initiatives. These papers provide a basis from which junior faculty members can design literature-informed program evaluations for their educational projects.


A total of 49 schools  participated in the Secondary 2 Program of the Experimental Implementation Phase of the Project P.A.T.H.S. . After completion of the Tier 1 Program, 270 instructors completed the Subjective Outcome Evaluation Form (Form B) to assess their views of the program, their own performance, and perceived effectiveness of the program. Based on the consolidated reports submitted by the schools to the funding body, the research team aggregated the consolidated data to form a “reconstructed” overall profile on the perceptions of the program implementers. Results showed that high proportions of the instructors had positive perceptions of the program and their own performance, and over 90% of the instructors regarded the program as helpful to the program participants. These findings are consistent with the subjective outcome evaluation findings based on the perspective of the program participants.


Museums have an untapped potential to engage students in hands-on learning. Here, we describe the development of a tiered museum-based program at the University of California, Berkeley as a model for engaging undergraduates in biodiversity science. This decade-long effort to increase student participation in collections demonstrates the mutual benefits of undergraduate involvement. Museums benefit from critical help in collections care and an increased intellectual vitality, while students simultaneously gain essential research skills and an unparalleled exposure to biodiversity. Five first steps to creating a program are: dedicate a coordinator, offer credit, diversify participation, create a tiered structure, and build community. Natural history museums have an incredible but largely untapped potential to facilitate undergraduate learning through specimen-based research and teaching ,2. AlthoThe past few decades have witnessed a tendency to de-emphasize undergraduate training in natural history, biodiversity science, and field biology ,7. This Undergraduates in museums have the opportunity to see and hold biodiversity in their hands. This kind of hands-on learning imparts students with an exceptionally deep understanding of ecology and evolution ,10. In aHere, we present an example of an exceptionally effective and in-depth program that incorporates active, hands-on learning in undergraduate education: the Undergraduate Program at the Museum of Vertebrate Zoology (MVZ), University of California, Berkeley. We detail the program’s structure as a model for engaging students in biodiversity science and conclude with several recommendations for other museums interested in developing similar programs.Use of a tiered structure  allows sThe MVZ program is open to all UC Berkeley students, who are recruited via multiple routes. This increases the applicant pool and attracts individuals with diverse backgrounds and interests . StudentAt the end of each semester, students and supervisors provide feedback that is used both to evaluate the program and to advance undergraduates through the tiered system . More exThe MVZ is not unique among museums in engaging undergraduates in curatorial and research activities . HoweverUndergraduates often take courses in biodiversity science that complement and enrich the program. A freshman seminar introduces new students to the collections and museum research opportunities. Many classes use specimens in lab exercises and incorporate field trips during which students connect what they’ve learned in the museum with vertebrates in their natural settings. For example, the century-old “Natural History of the Vertebrates” course at UC Berkeley  has weekThe museum’s central location on the Berkeley campus makes it easier to involve students because they can work in the collections between classes. In an era when multiple university collections have been eliminated or moved offsite , the larOne of the most popular opportunities in the program is to work as a preparation lab assistant  or to taUndergraduates also have opportunities to participate in regional and international fieldwork. Through such trips, which can provide a transformative experience via active learning, students are exposed to field methods and diverse wildlife . In addiCreating and maintaining a program of this type requires planning, creativity, dedication, and ongoing investment. Ultimately, the results are well worth the effort, as evidenced by the outcomes we describe here. Undergraduates now perform much of the museum’s curatorial activities , includiUndergraduate participation enriches the broader impacts of grant proposals and helps to attract more funding through increased research productivity. For example, undergraduate field assistants facilitate the collection and curation of an expanded suite of samples  and associated data , thereby enhancing the value of each specimen. Likewise, undergraduates with molecular lab training help to increase the amount of genetic data captured from museum specimens.http://amphibiaweb.org), a web portal for amphibian biology, conservation, and taxonomy that has broad benefit to the scientific community and continues to grow due to the contributions of student writers and editors. More generally, undergraduate engagement helps to train the next generation of science, technology, engineering, and math (STEM) researchers and to create well-educated, scientifically literate citizens who can become future advocates for biodiversity and museums.In addition to these practical benefits, undergraduates enhance the vitality of the museum through their intellectual energy by asking questions and contributing ideas, which brings new perspectives to biodiversity science. For example, undergraduates were involved in the conception of AmphibiaWeb “[In the MVZ] my first two projects were ‘weeder’ projects, to assess how closely I paid attention to detail. The first was to sort through the reprint collection and alphabetize reprints. I still remembered the authors of those reprints and what the studies were about when I attended my first society meeting, and I was able to hold conversations with established professors as an undergraduate.”–High School Biology Teacher (2 years in the MVZ)“The MVZ Undergraduate Program helped me to discover my love for the process of science and led me to grad school to continue my exploration. In grad school, I discovered my passion for teaching which led to my career as a high school biology teacher in which I get to engage students in scientific research by teaching them how to DO science the way that the MVZ program taught me.”–Geographic Information System (GIS) Analyst, Environmental Nonprofit (3 years in the MVZ)“I happened upon fieldwork with the MVZ and have been hooked on birds since. At the MVZ, I found an engaging community of amazing researchers, graduate students, and undergrads just getting their feet wet like me … The love and enthusiasm professors and graduate students had for biodiversity and evolution was what inspired me to become a biologist.”–California State Archivist (4 years in the MVZ)“Working with the MVZ’s historic field notebooks, photographs and annotated maps introduced me to the joys of interacting directly with historically significant primary sources … It was thrilling to dig through the field notebooks, photographs, and annotated maps of past MVZers, extracting stories that contextualized the museum’s specimens and brought to life the often entertaining and sometimes harrowing experiences of researchers out in the field over the last century.”––Medical Student (3 years in the MVZ)“I entered UC Berkeley without any idea of what I wanted to major in, much less what I wanted to go into for a career. The community I found by joining the MVZ Undergraduate Program was with me every step of the way as I explored options ranging from pharmacy to graduate school to finally medical school.”Biologist, Environmental Consulting Firm (1 year in the MVZ)“In the MVZ I remember seeing a walrus skull, a poison dart frog, and a shoebill stork in the span of 15 minutes. The sheer biodiversity contained only within the museum is absolutely astounding, and seeing specimens in the museum as well as in the field creates an incredibly comprehensive learning experience for aspiring biologists.”–Research has shown that peer mentoring and active learning improve student performance in STEM courses, especially among undergraduates from groups underrepresented in science ,22,23. Fhttp://bsp.berkeley.edu). BSP is a community support network and mentorship program for undergraduates from groups who face extra barriers to the sciences, including first-generation college students, individuals from economically disadvantaged backgrounds, and students from underrepresented minorities [Notably, creating a structured, formalized program has allowed the museum to forge links with other targeted initiatives such as Berkeley’s Biology Scholars Program .Moving forward, we plan to more rigorously evaluate the benefits of this type of biodiversity science-based undergraduate program through formal assessments. For example, use of the Knowledge of Evolution Exam (KEE)  will allAs current museum scientists and wildlife professionals retire ,33, the S1 Fign = 384) enrolled in the MVZ Undergraduate Program between 1 June 2005 and 31 May 2015 represented 38 different majors. MVZ, Museum of Vertebrate Zoology; URAP, Undergraduate Research Apprentice Program.URAP students ((JPG)Click here for additional data file.S2 FigShows the paths that students take during their training in the MVZ and their subsequent, post-graduation career tracks. Red circles represent MVZ positions, blue circles represent post-graduation positions. Node sizes represent the relative number of individuals engaged in each job. MVZ, Museum of Vertebrate Zoology.(JPG)Click here for additional data file.S1 Text(DOC)Click here for additional data file.S2 Text(DOC)Click here for additional data file.S3 TextMVZ, Museum of Vertebrate Zoology.(DOCX)Click here for additional data file.S4 Text(DOCX)Click here for additional data file.


In 2009, the international Stop Transmission of Polio (STOP) program began supporting the Global Polio Eradication Initiative in the Republic of South Sudan to address shortages of human resources and strengthen acute flaccid paralysis surveillance. Workforce capacity support is provided to the South Sudan Expanded Program on Immunization by STOP volunteers, implementing partners, and non-governmental organizations. In 2013, the Polio Technical Advisory Group recommended that South Sudan transition key technical support from external partners to national staff as part of the Polio Eradication and Endgame Strategic Plan, 2013–2018. To assist in this transition, the South Sudan Expanded Program on Immunization human resources development project was launched in 2015. This 3-year project aims to build national workforce capacity as a legacy of the STOP program by training 56 South Sudanese at national and state levels with the intent that participants would become Ministry of Health staff on their successful completion of the project. Decades of civil war in South Sudan have resulted in the collapse of its infrastructure and public health system. The impact of this war on the immunization program was evident when the diphtheria-tetanus-pertussis (DTP) coverage was documented at 10% in 2004 [After the signing of the comprehensive peace agreement, the government of South Sudan began to rebuild its healthcare system. In 2006, it released its “Health Policy for the Government of Southern Sudan,” which provided early guiding principles for the restructure of South Sudan’s public health system . The SouThrough multilateral efforts, the DTP3 coverage rate for children <1 year old, as shown by administrative data, improved from 10% in 2004 to 22% in 2008 and then to 71% in 2010, with a decline in DTP1-DTP3 dropout rate from 41% to 27% over the same period .The importation of WPV was most likely due to massive displacement of refugees during the civil war and low routine immunization (RI) coverage. Implementation of supplemental immunization activities (SIAs), including national immunization days and mop-up campaigns, contributed to South Sudan’s being free of WPV transmission since June 2009. This achievement and a need to update the cMYP for 2012–2016 led to an external comprehensive review of the Expanded Program on Immunization (EPI) in 2011 to document key milestones achieved and lessons learned over the years and to identify weaknesses and threats to the EPI.Despite major challenges in the country, results of the 2011 EPI review revealed several accomplishments of the program . However, major gaps and challenges were also noted. One key challenge documented was the paucity of qualified staff working on immunization-related activities within all levels of the healthcare system. More than 80% of required EPI positions at national level and 50% of required EPI positions at the state level were vacant . Very feThe STOP program is one of the pillars of the Global Polio Eradication Initiative (GPEI). It was conceptualized and implemented in 1999 by the US Centers for Disease Control and Prevention (CDC) in collaboration with WHO to address shortages of human resources and to strengthen technical assistance for polio eradication and other immunization activities in polio-endemic countries . The proSTOP is a volunteering program that recruits master’s and/or doctoral level public health professionals with ≥5 years of work experience in capacity building; vaccine-preventable disease (VPD) surveillance for acute flaccid paralysis (AFP), measles, and rubella; health communication and/or social mobilization; and health information systems, specifically with immunization and VPD surveillance data. Under the leadership of WHO, STOP began supporting the GPEI in South Sudan in 2009 by deploying 20 international volunteers to conduct field assignment for a period of 4–6 months. Continuous deployment of STOP volunteers in the same region or area of the country has been the practical norm. The STOP volunteers are allowed to do a maximum of 4 assignments in the program.From 2009 until present, a total of 57 STOP volunteers were deployed in South Sudan to focus on core areas of the EPI. Of this number, 41 field epidemiologists were deployed on 203 assignments, 5 data managers on 28 assignments, and 11 communication specialists on 21 assignments. These STOP volunteers were placed to fill gaps and provide overall support to the local EPI. Over the years, they have established and supported community-based surveillance, implemented polio national immunization days, supported RI and SIAs, improved data management and quality, and provided other immunization-related activities as needed.In addition to the critical technical support provided by implementing partners and non-governmental organizations, the STOP program has positively contributed to the overall performance of the South Sudan EPI program and its workforce capacity. The 2013 STOP global evaluation team documented that the long-term impact of the STOP program on South Sudan EPI program  is credited to the continuous deployment of STOP volunteers to the same location . Within The STOP program is a hybrid of capacity-building and capacity-filling strategies for health systems strengthening. Of 17 STOP volunteers interviewed in South Sudan in 2013, 9 reported most of their time spent on capacity-filling activities , compared to 8 who focused on capacity building  [In collaboration with WHO’s South Sudan country office, the MOH developed a proposal in 2013 outlining the overall goal and objectives of a workforce capacity development project, which estimated ongoing staffing needs and outlined essential EPI-related functions that would need to be strengthened to build a functional national program. The proposal was later presented to the CDC and UNICEF for potential collaboration. This initiative led to a strong multilateral partnership to strengthen workforce capacity for the South Sudan EPI.In collaboration with the CDC, WHO, UNICEF, and the African Field Epidemiology Network (AFENET), the MOH launched the Human Resources Development for South Sudan EPI to achieve polio endgame milestones in 2015. The overall goal of this project is to contribute to the development of an adequately staffed and trained EPI workforce in South Sudan at the central and state/administrative levels. Its aim is to train 56 South Sudanese for the national and state levels on RI, VPD surveillance, SIAs, data management, communication, and cold-chain logistics. During the project, one of the primary roles of the STOP volunteers would be to provide ongoing mentorship to the program’s participants. The MOH estimated approximately 8 vacant positions at the national level and 6 vacant positions at each state/administrative area level within the EPI core functions . The intention is for those trainees who successfully completed the program to be vested as full-time employees of the EPI unit within the MOH for ≥3 years. It is expected that >85% of the vacant positions at the national level will be filled (approximately 7 of 8 participants). The remaining 48 trainees will be equally distributed among the 12 states/administrative areas; therefore, 50%–67% positions will be filled (3–4 of 6).An AFENET technical advisor was recruited to oversee the project and to provide mentorship and supervision to the program’s participants. In collaboration with MOH, WHO, and CDC, the technical advisor is also responsible for the development and implementation of the training curriculum based on desired competencies and for providing technical guidance and direction to the participants, including refresher training as needed.Participants are recruited from their respective state of residence in coordination with their state MOH levels, WHO, UNICEF, and the in-country technical advisor. Overall, 8 mentees will be recruited from the central level and 3–5 mentees for each state/administrative area depending on agreed-on EPI needs . Given tTraining is ongoing by state/administrative level and adjusted for different recruitment timelines. All recruited participants have received a 1-week comprehensive induction training on EPI regardless of their background in immunization and/or public health. Additional training is provided based on their areas of specialty . The conThe learning experience of the participants is not homogeneous, but it is dependent on geographic location, areas of specialty, and response to specific events, such as occurrence of a measles outbreak in a given area. The second and third years of this project will focus on reinforcing acquired competencies of the participants. Ad hoc classroom refreshers and competency-based trainings are provided as needed.On completion of the 1-week induction training, the participants are deployed to their assigned sites at the central, state, and administrative levels of the MOH. They receive weekly on-the-job training while in the field, focusing on individual competencies. Field assignments and training topics vary based on the participant’s core EPI focus. For example, a participant whose concentration is RI would receive training on the “reaching every district” approach and EPI service delivery microplanning and would be expected to develop locally relevant microplans and plans for program monitoring and supervision. In contrast, participants whose focus is on cold-chain management would work on the cold-chain maintenance, develop cold-chain replacement and expansion plans, and update cold-chain equipment inventories. Participants are required to provide weekly updates to the technical advisor on their progress with specific assigned tasks.STOP volunteers and other WHO EPI consultants serve as technical mentors for activities, such as SIAs, RI, case-based surveillance for VPDs, and EPI monitoring. Similarly, UNICEF staff and STOP volunteers serve as technical mentors in EPI communication, cold-chain management, and effective vaccine management. All state-level field mentorship activities are under the supervision of the MOH project coordinator, national and state EPI managers, and the technical advisor. Bill & Melinda Gates Foundation representatives in the states of Jonglei and Upper Nile also provide mentorship to participants.Since the inception of this project, 8 central-level participants were deployed to the field to participate in the meningococcal vaccine SIAs. Furthermore, both central and state-level participants have supported measles outbreak responses in the states of Agok, Mayom, and Gogriel by collecting surveillance and case-based data, creating line lists from selected state and county hospitals to inform response planning, and monitoring postoutbreak response.Mentoring workshops on preselected immunization-related topics have been conducted weekly. Examples of topics for these weekly mentoring workshops include measles outbreak response and risk analysis, the role of national immunization technical advisory group operations, the switch from trivalent to bivalent oral poliovirus vaccine, sentinel site vaccine utilization monitoring, EPI operations microplanning, and competency-specific training .The participants have applied competencies developed through these workshops in several ways. For example, the workshop focusing on the switch from trivalent to bivalent oral poliovirus vaccine prepared the participants to support activities related to the switch. Training in microplanning for EPI operations fed into the development of context-relevant microplans to boost EPI coverage required by Gavi, the Vaccine Alliance’s health system strengthening funding. Four communication-for-development participants field-tested a defaulter tracing interview tool aimed at generating behavioral surveillance data to be used for an upcoming project on communication. The communication-for-development, SIA, and RI operations participants participated in a UNICEF-specific training on development of a communication strategy for conflict-affected areas. Cold-chain technician participants have received certified training in installation and maintenance of solar direct-drive refrigerators. As a result, they supported installation of 10 solar refrigerators in the Greater Central Equatoria and completed assessment of cold-chain equipment in that area. They have already repaired 22 EPI refrigerators, 4 ice-pack freezers, and 3 deep freezers, and will continue to repair all EPI refrigerators and freezers in a systematic and scheduled maintenance plan being developed by the MOH.Implementation of this project and its progress are being monitored routinely and will culminate with a yearly program assessment to evaluate implementation and progress with planned activities. The monitoring and evaluation plan and framework as well as standardized tools are being finalized to capture an in-depth understanding of participants’ progress with skills and knowledge acquisition in their core competency areas. Results of monitoring and evaluation activities will inform project implementation, including activities of the participants in the field.Implementing this project has not been an easy feat. Ongoing security issues have hampered movement to different regions of the country and even within states. Consequently, some implementing partners have not been able to visit the country since implementation to provide direct technical support. Moreover, the recent creation of 16 additional states has substantially changed the recruitment process and scope of the project. This change has led to a delay in the recruitment timeline. Constraints imposed by ethnic and tribal tensions have also restricted movement of participants. For example, participants from Central Equatoria state cannot safely move to Terekeka state, which was recently created to be a state dominated by the Mundari ethnic group.The Republic of South Sudan has been identified by the GPEI as high risk for poliovirus importation from neighboring countries. In the event of an importation, field activities will be modified to reflect the current situation on the ground. The transition plan from a polio-free world to other health programs is not yet finalized in South Sudan; however, this project will fit well into the transition plan.The principle objective of this project is to develop a qualified, skilled, and sustainable cadre of immunization public health workers. The project is designed to build on the legacy of the international STOP program to develop and sustain national workforce capacity. Its approach is collaborative and leverages a broad range of partnerships and expertise to advance the South Sudan EPI’s main objectives and priorities , respond to other public health emergencies, and strengthen RI.The project highlights the feasibility of building national workforce capacity in a country with multiple challenges, including security issues and ethnic conflicts. It serves as a platform to share and exchange knowledge, ideas, and experience on strengthening human resources capacity, using nationals as a sustainable approach instead of international consultants to temporarily fill human resource gaps. Given that this project is still in its infancy stage, lessons learned from it will be documented at a later date.Depending on the evolution of this project and the political stability of the country, there may be a possibility to expand the project to build future capacity at the county/district levels, where most operations and actions for improving immunization coverage take place. This would also enable provision of enhanced RI support to hard-to-reach and high-risk areas. The long-term sustainability of the project is clearly dependent on the country’s political stability and the degree of political and financial commitment to the immunization program by the government of South Sudan. Nevertheless, stakeholders and the team remain committed to the success of this project and to the overall goal of building a strong immunization public health workforce capacity in South Sudan.


Purpose To assess effects of an inpatient multicomponent occupational rehabilitation program compared to less comprehensive outpatient rehabilitation on sickness absence in persons with musculoskeletal- or mental health disorders. Methods Randomized clinical trial with parallel groups. Participants were individuals 18–60 years old on sick-leave for 2–12 months with a sick-leave diagnosis within the musculoskeletal, psychological or general and unspecified chapters of ICPC-2, identified in a national register. The inpatient program (4 + 4 days) consisted of Acceptance and Commitment Therapy (ACT), physical training and work-related problem-solving including creating a return to work plan and a workplace visit if considered relevant. The outpatient program consisted primarily of ACT (6 sessions during 6 weeks). Both programs were group based. Primary outcome was cumulated number of sickness absence days at 6 and 12 months follow-up. Secondary outcome was time until sustainable return to work. Results 168 individuals were randomized to the inpatient program (n = 92) or the outpatient program (n = 76). We found no statistically significant difference between the programs in median number of sickness absence days at 6 and 12 months follow-up. In the outpatient program 57% of the participants achieved sustainable return to work (median time 7 months), in the inpatient program 49% . The hazard ratio for sustainable return to work was 0.74 , in favor of the outpatient program. Conclusions This study provided no support that the more comprehensive 4 + 4 days inpatient multicomponent occupational rehabilitation program reduced sickness absence compared to the outpatient rehabilitation program. Too many people leave the workforce prematurely due to health problems or disability, and too few workers with health problems are able to stay in work , particuSeveral treatment and rehabilitation programs to facilitate work participation have been investigated, notably for persons with low back pain, but also for common mental disorders –6. HowevThe diagnosis-specific emphasis of previous studies –5, 9, 21Although inpatient occupational rehabilitation programs in Norway typically last about 4 weeks where patients live at the centers, there are several reasons for investigating different approaches: (1) in a pilot-investigation, several participants reported that 4 weeks was too long to stay away from home; (2) a continuous stay at a rehabilitation center does not allow for workplace involvement, and (3) a 4-week rehabilitation period is based on traditions rather than scientific evidence, and less costly alternatives should be investigated. Hence, we designed a randomized study investigating effects on sick leave of an inpatient multicomponent occupational rehabilitation program lasting 4 + 4 days, separated by 2 weeks where a workplace visit could be performed. The comparative program was a less comprehensive outpatient program, consisting mainly of a recent form of cognitive behavior therapy . We hypohttps://clinicaltrials.gov/ (No.: NCT01926574). The results are presented according to the CONSORT statement [We conducted a randomized clinical trial with parallel groups, comparing an inpatient multicomponent occupational program with a single-component outpatient program  for individuals on sick-leave due to musculoskeletal-, unspecific-, or common mental health disorders. Details about the study design have been published in a protocol article . The stuEligible participants were 18 to 60 years of age sick listed 2 to 12 months with a diagnosis within the musculoskeletal (L), psychological (P) or general and unspecified (A) chapters of the ICPC-2 . The current sick leave status had to be at least 50% off work. Exclusion criteria, assessed by a comprehensive questionnaire and an outpatient screening performed by a physician, physiotherapist and psychologist, were: (1) alcohol or drug abuse; (2) serious somatic  or psychological disorders ; (3) specific disorders requiring specialized treatment; (4) pregnancy; (5) currently participating in another treatment or rehabilitation program; (6) insufficient oral or written Norwegian language skills to participate in group sessions and fill out questionnaires; (7) scheduled for surgery within the next 6 months; and (8) serious problems with functioning in a group setting.The inpatient program consisted of several components; group-based cognitive behavioral therapy, individual and group-based physical training, mindfulness, psychoeducation on stress and individual meetings with the coordinators for work-related problem-solving and creating a return to work plan. The cognitive behavioral approach was Acceptance and commitment therapy (ACT), which is a new form of cognitive behavioral therapy that emphasizes accepting both negative and positive experiences while using the individuals` values to guide them towards their goals [ir goals . Studiesir goals , anxietyir goals  and deprir goals , 29. Thrir goals  and to iir goals . ACT wasir goals .The intervention lasted four full workdays in week 1 and week 4  during which the participants resided at the rehabilitation center, separated by 2 weeks at home (week 2 and 3). The 2 weeks at home included at least two contacts with the team coordinator (in person or by telephone) and a meeting with the employer if regarded relevant and the participant gave permission. The coordinators who mentored the participants were supervised by a certified ACT-instructor before and during (monthly) the intervention. The program took place at Hysnes rehabilitation center, established as part of St. Olavs Hospital, in central Norway.The outpatient program consisted primarily of one component; group-based ACT. The sessions were held at the Department of Physical Medicine and Rehabilitation at St. Olavs Hospital once a week for 6 weeks, each session lasting 2.5 h. The sessions were led by either one of two physicians  or a psychologist; all supervised by the same ACT instructor as the coordinators in the inpatient program. The participants were given assignments to practise at home between sessions, including a daily 15 min audio-guided mindfulness practice. In addition the participants were offered two individual sessions with a social worker experienced in occupational rehabilitation and trained in ACT to clarify personal values and work-related issues. The program also included a motivational group discussion with a physiotherapist on the benefits of physical training. An individual session with both the social worker and group leader present ended the program. In this session a summary letter was written to the participant’s general practitioner.All legal residents in Norway are included in the Norwegian public insurance system. Medically certified sick leave is compensated with 100% coverage for the first 12 months. The first 16 days are covered by the employer, the rest by the Norwegian Welfare and Labour Administration. After 12 months of sick leave it is possible to apply for the more long-term medical benefits, work assessment allowance and disability pension, which both covers approximately 66% of the income. Individuals on work assessment allowance are supposed to work according to their workability.Participants were followed for 12 months after inclusion. During this period, sickness absence was registered in monthly intervals, both as number of days per month and as a dichotomous measure of whether or not the participant was registered on sick leave that month. Outcomes were measured using data from the National Social Security System Registry, where all individuals receiving any form of benefits in Norway are registered by their social security number. The data consisted of registrations of medical benefits from four different sources; sick-leave payments, sick leave certificates, work assessment allowance and disability pension. Monthly intervals (rather than exact dates) were used in order to include all relevant sick leave benefits in the same measure, as exact dates were not available for payments and the long-term benefits. Work assessment allowance was adjusted for delay in payments up to 2 months.The primary outcome measure was cumulated number of sickness absence days, calculated at 6 and 12 months after inclusion. By combining information from the different medical benefits we calculated days on medical benefits (according to a 5-day work week) for every month during follow-up. Time on graded sick leave was transformed to whole workdays. Days receiving sick-leave payment and work assessment allowance were adjusted for employment fraction, including a graded disability pension at inclusion. Any increase in disability pension during follow-up was counted as sick leave.The secondary outcome measure was time until full sustainable return to work defined as 1 month without relapse, i.e. one monthly interval not receiving any medical benefits (except any graded disability the participant had when entering the study).Questionnaires measuring baseline characteristics like education, pain, anxiety and depression symptoms were answered by the participants before the screening. Anxiety and depression were assessed using The Hospital Anxiety and Depression Scale (HADS) . It consInvited participants completed a short questionnaire assessing initial eligibility. Those eligible were invited for an outpatient screening assessment. If the screening was passed Fig. , subjectSample size calculations were based on three approaches :Comparison of RTW with Kaplan Meier survival analysis with log rank test with a hazard ratio of 0.6  would require 63 in each group.Comparison of number of days with sick leave at 6 months of follow-up : An average of 60 days (SD 40) and 90 days (SD 60) of sick leave in the intervention and comparative group, respectively would require 61 persons for each group.Comparing ratios of participants at work after 1 year of follow-up with the same statistical assumptions as point 2; and a difference of 60 versus 40% RTW, would require 63 people in each group.With an estimated 20% loss to follow-up we aimed to include 80 persons in each arm. The sample size calculations were based on results from previous studies in this field , 9, 10.Number of days of sick leave at 6 and 12 months after inclusion for the two programs were calculated and compared using the Mann–Whitney U (Wilcoxon rank sum) test. For time until sustainable return to work Kaplan Meier curves were estimated and compared with the log rank test. We estimated hazard ratios for return to work using Cox proportional hazard model with the Efron method for ties . Time waIn addition to the main analyses, we performed several post hoc sensitivity analyses in order to account for characteristics of the sickness absence patterns and data structure which we observed in the course of the study. First, we observed that several participants alternated between being on and off benefits. We therefore performed a repeated events analysis allowing individuals to alternate between being on and off benefits every month of follow-up using general estimating equations (GEE). Secondly, we observed single months without payment in between longer periods of payments. As the Norwegian holiday lasts 5 weeks, we performed an additional sensitivity analysis on time until sustainable return to work where we defined return to work as 2 months without benefits.We considered p-values (two-tailed) <0.05 to be statistically significant. Precision was assessed using 95% confidence intervals. All analyses were done using STATA 13.1 .The flow of participants through the study is illustrated in Fig. For the inpatient program, 14 people withdrew before they began the program and four quit during the program. For the outpatient program, five people withdrew before the program started and eight during the program. Those who started the outpatient program attended on average 7.9 of the 10 meetings and 59 (83%) attended at least 60% of the sessions. For the inpatient program there is no data available regarding the number of sessions participants attended, but as it was an inpatient program the participants were assumed compliant if they did not withdraw. All participants were included in the analyses. A workplace visit was performed for 13% (n = 10) of the participants who started the inpatient program.Most of the participants (65%) worked full time prior to their sick-leave, while 18% worked part time, 4% had a graded disability pension and 13% had no job. The median number of days on sick-leave the last 12 months before inclusion in the study (i.e. second randomization) was 226 calendar days (interquartile range (IQR) 189–271). A musculoskeletal diagnosis was most common (52%), followed by psychological (38%) and general and unspecific (10%) diagnoses. The mean age of participants was 45 years and the majority was women (79%). The baseline characteristics of the participants in the two programs were fairly similar (Table The median number of sickness absence days (work days) at 6 months after inclusion was 58 IQR 37–92) for the inpatient program and 51 (IQR 32–85) for the outpatient program. The difference was not statistically significant . For the 12 months follow-up, the median number of sickness absence days was 114 (IQR 46–172) for the inpatient program and 96 (IQR 35–175) for the outpatient program  during 12 months follow-up, 45 participants (49%) in the inpatient program and 43 participants (57%) in the outpatient program. Median time until sustainable return to work was 7 months for the outpatient program (IQR 4-not reached). The inpatient program did not reach 50% return to work in the follow-up period (IQR 5-not reached). Figure Of the participants achieving sustainable return to work, 15 participants (33%) in the inpatient program and 20 (47%) participants in the outpatient program returned to medical benefits during the 12 months follow-up. At 12 months, 40 participants (43%) in the inpatient program and 30 (39%) in the outpatient program was not on medical benefits (excluding graded disability benefits). About half the participants received work assessment allowance in both groups (50 and 49% respectively) and 5% of the participants in the inpatient program and 12% in the outpatient program were on sick leave. One participant in the inpatient program received full disability pension.Repeated events analyses for return to work showed no difference between the programs at any of the time points (months of follow-up) Fig. . The aveWhen the analyses were performed using 2 months without medical benefits as event, the sustainable return to work rate dropped slightly to 45 and 53% for the inpatient and outpatient program respectively. Unadjusted and adjusted cox regression gave hazard ratios similar to the analyses performed with1 month without benefits as the event.Per protocol analyses comparing number of sickness absence days in the inpatient and outpatient programs showed similar results as the main analyses at 6 months: 60 (IQR 39–96) versus 53  days and at 12 months: 118 (IQR 48–181) versus 98  days. The per protocol cox regression analyses also showed similar results as the main analyses: unadjusted HR 0.71 , and adjusted HR 0.70 .Among persons on sick leave with a musculoskeletal, psychological or unspecific diagnosis, this randomized trial showed no significant difference in number of sickness absence days and time to sustainable return to work following an inpatient multicomponent occupational rehabilitation program compared to a less comprehensive outpatient program.Even though there were no statistical differences between the programs, there were some indications that participants in the outpatient program had less sickness absence days and shorter time to sustainable return to work. However, this group also had a higher fraction of recurring sickness episodes. Hence, we performed a post hoc analysis to assess the probability of receiving/not receiving monthly medical benefits throughout the 1-year follow-up period. Assessing sickness absence in this way made the between-group differences smaller, strengthening the finding of no difference between the programs.Return to work rates in this study were lower than in some previous return to work studies , 5, 6. HStudies have suggested that involving the workplace in return to work programs is effective for reducing sick leave for individuals on sick leave with low back pain , 9 and cIn a Norwegian context this was a relatively short inpatient occupational rehabilitation program (4 + 4 days), as traditional inpatient programs typically last about 4 weeks . In thatThe main strength of this randomized study was the use of registry data on medical benefits, ensuring that there were no biased assessments of end-points and no missing data. Furthermore, all participants were invited from the National Social Security System, meaning there was no referral bias. However, there was a self-selection bias as to which individuals accepted the invitation to participate in the study. Accepting the invitation meant they had to be prepared to be away from family and friends during the program if allocated to the inpatient program. From more than 3000 invitations sent, only 275 individuals accepted the invitation, which limits the generalizability of the results. Even though an inclusion criterion was sick leave for at least 8 weeks, the mean length of sick leave at inclusion was more than 220 days for both programs. It could be that individuals with greater obstacles for return to work to a larger extent accepted the invitation. This assumption is strengthened by the fact that around 50% of the participants received work assessment allowance at 12 months follow-up. As this medical benefit provided after 1 year of sickness absence only reimburses 66% of the salary compared to 100% for sick leave pay, there is a considerable financial incentive for returning to work within 1 year. As there is no randomized usual care control group we do not know if the programs reduced sick leave and increased return to work compared to usual care. Another limitation was that the researchers were not blinded. However, sickness absence was registered and provided by employees at the Norwegian Welfare and Labor Service whom were unaware of group allocation.Among persons on sick leave with a musculoskeletal, psychological or unspecific diagnosis, this study provides no support that the 4 + 4 days inpatient multicomponent occupational rehabilitation program reduces sickness absence compared to a less comprehensive outpatient program. As the inpatient program was more resource-demanding we do not recommend it to be implemented in regular clinical practice. Considering that this program was relatively short in an inpatient setting, future studies should investigate effects of more extensive inpatient occupational rehabilitation programs.


The Tier 2 Program of the Project P.A.T.H.S.  is designed for adolescents with significant psychosocial needs, and its various programs are designed and implemented by social workers (program implementers) for specific student groups in different schools. Using subjective outcome evaluation data collected from the program participants (Form C) at 207 schools, the program implementers were asked to aggregate data and write down five conclusions  in their evaluation reports. The conclusions stated in the evaluation reports were further analyzed via secondary data analyses in this study. Results showed that the participants regarded the Tier 2 Program as a success, and was effective in enhancing self-understanding, interpersonal skills, and self-management. They liked the experiential learning approach and activities that are novel, interesting, diversified, adventure-based, and outdoor in nature. They also liked instructors who were friendly, supportive, well-prepared, and able to bring challenges and give positive recognition. Most of the difficulties encountered in running the programs were related to time constraints, clashes with other activities, and motivation of participants. Consistent with the previous evaluation findings, the present study suggests that the Tier 2 Program was well received by the participants and that it was beneficial to the development of the program participants.


Immunoglobulin G (IgG) against the NR1-subunit of the N-methyl-D-aspartate (NMDAR) receptor mediates NMDAR-antibody encephalitis (NMDAR-Ab-E). This multi-stage illness presents with an acute severe psychiatric syndrome, alongside other neurological features, similar to human and animal NMDAR antagonist models. The disease is associated with an ovarian teratoma in around 20% of cases. The cellular immunity underlying this disease is not well understood. While antibody-modifying immunotherapies often promote disease resolution, the illness can be refractory to these treatments correlating with sub-optimal outcomes.NR1-IgG can be detected several years after clinical resolution, which may be via ongoing germinal centre reactions or the establishment of antibody-secreting cells as long-lived plasma cells in bone marrow niches. These two divergent models implicate use of differing immunotherapies to target these cells. Here we investigate the contribution of ongoing germinal centre reactions to disease progression, potentially informing disease mechanisms and guide targeted immunotherapy.We hypothesised that recurrent antigen-driven germinal centre reactions would be associated with active generation of NR1-specific IgM and IgG and NR1-specific circulating B cells. We validated a NR1-IgM cell based assay establishing specificity cut-offs by screening healthy and disease control cohorts alongside a previously collected NMDAR-Ab-E cohort (n=46). Following this we went on to explore the temporal evolution of NR1-IgG and NR1-IgM titres in a prospective cohort (n=12).To investigate the lymphocyte characteristics, we stimulated ovarian teratoma lymphocytes and peripheral blood mononuclear cells (PBMCs) from multiple time points under varying cytokine conditions to understand whether these circulating cells showed capacity for NR1-IgG and IgM generation.We found a 43% prevalence rate of NR1-IgM in the historic cohort. We then confirmed that NR1-IgM binding was specific by its selective depletion after anti-IgM precipitation but not with protein G. In the prospective cohort, we noted often high titres of IgM (up to 1:500) most commonly early in the disease but persisting for around 2 years. NR1-IgM levels varied in titre alongside NR1-IgG spikes. Consistently, culture experiments of patient lymphocytes (PBMCs and tumour-derived) produced varying degrees of NR1-IgM and NR1-IgG under conditions associated with B cell proliferation. The NR1-IgG levels correlated with serum NR1-titres suggesting these circulating B cells made a proportional contribution to serum levels.Ongoing germinal centre reactions likely contribute much of the circulating NR1-specific B cell population in NMDAR-Ab-E. Autoimmunisation at these centres represents an as yet unexplored therapeutic target in this and potentially other autoimmune encephalopathies. Regional specificity of these reactions including lymph nodes draining sources of NR1-antigen require further direct evaluation.


Quaking-5 (QKI-5) belongs to the STAR  family of RNA binding proteins and functions as a tumor suppressor in several human malignancies. In this study, we attempt to elucidate the role of QKI-5 in the pro-metastasis processes of lung cancer (LC) cells and the underlying mechanisms. We confirmed that QKI-5 was decreased in human LC tissues and cell lines, especially in high-metastatic cells. Moreover, QKI expression was positively correlated with LC patients’ survival. Functional studies verified that QKI-5 suppressed migration, invasion and TGF-β1-induced epithelial-mesenchymal transition (EMT) of LC cells. Mechanistically, we affirmed that QKI-5 reduced β-catenin level in LC cells via suppressing its translation and promoting its degradation, whereas QKI-5 promoter hypermethylation suppressed QKI-5 expression. Our findings indicate that QKI-5 inhibits pro-metastasis processes of LC cells through interdicting β-catenin signaling pathway, and that QKI-5 promoter hypermethylation is a crucial epigenetic regulation reducing QKI-5 expression in LC cells, and reveal that QKI-5 is a potential prognostic biomarker for LC patients. Lung cancer (LC) currently ranks as one of the most prevalent neoplasms and the leading cause of cancer-related deaths worldwide . AccordiAs is known, metastasis occurs in about 40% of newly diagnosed LC patients . EpithelQKI gene encodes three major alternatively spliced mRNAs, i.e., QKI-5, QKI-6, and QKI-7 with different C-terminals. QKI-5 is prominently expressed in early embryogenesis, while QKI-6 and -7 are mainly expressed in the central nervous system in late development stage [[N1–20]UAAY) in the 3′-UTR of mRNA, QKI impacts diverse aspects of target mRNAs including the location, stability, and translational efficiency in multiple physiological and pathological processes [NUMB and MacroH2A1 [Quaking (QKI), a member of signal transduction and activation of RNA (STAR) protein family, is a pivotal post-transcriptional regulator . The QKInt stage . Throughrocesses . In LC, rocesses , and itsacroH2A1 , 16. HowQKI promoter hypermethylation. Our data demonstrate for the first time that QKI-5 is a key inhibitor of LC cell aggressiveness and that methylation of QKI promoter contributes to QKI-5 downexpression in LC.In the present study, we confirm that QKI-5 is decreased in human LC tissues and cell lines, especially in high-metastatic cells, and identify that QKI-5 inhibits the migration, invasion and TGF-β1-induced EMT of LC cells by directly decreasing β-catenin. Moreover, we uncover that QKI-5 reduction in LC cells results from QKI mRNA expression predicted a shorter overall survival  and 20 LC samples with lymph node metastasis (LNM)). In comparison with non-cancerous lung tissues, QKI-5 mRNA reduction was more obvious in metastatic tumors than those of non-metastatic tumors , which was accompanied by the decrease of QKI-5 protein and E-cadherin as an epithelial marker, and increase of N-cadherin and Vimentin as mesenchymal markers , accompanied by the increase of N-cadherin and Vimentin . As show, accompaP<0.001; Figure P<0.01∼0.001; Figure P<0.01∼0.001; It has been previously reported that NSCLC H1299 cells are converted to fibroblastic phenotype in response to TGF-β1. To ascertain the role of QKI-5 in LC cell EMT, we conducted the experiment inducing EMT with TGF-β1 (5 ng/ml). At 48 h after induction, H1299-vector control cells showed spindle fibroblast-like morphology with reduced cell-cell contact and appeared more significant at 72 h, whereas QKI-5-overexpressing H1299-QKI-5 cells still remained epithelial shape at 48 h after induction and only exhibited minor morphological alteration at 72 h Figure . qRT-PCRP<0.001; Figure c-myc, cyclin D1 and MMP2 are the genes activated by β-catenin. Western blotting verified that β-catenin, c-myc, cyclin D1 and MMP2 were synchronously increased in QKI-5-silenced A549 cells, and decreased in QKI-5-overexpressing H1299 cells, while β-catenin knockdown or overexpression could effectively reverse the above effects of QKI-5 knockdown or overexpression on c-myc, cyclin D1 and MMP2 expressions  can catalyze β-catenin phosphorylation at Ser33/Ser37/Thr41 (p-β-catenin) and initiates p-β-catenin ubiquitin- dependent degradation. Western blotting analyses showed that β-catenin was reduced or increased, but the levels of DKK3, DVL1, DVL3 and GSK3β, the key regulators of Wnt/β-catenin signaling pathway, were constant in QKI-5-overexpressing or -silenced LC cells Figure . In contβ-catenin mRNA transcription in two LC cells  confirmed that flag-tagged QKI-5 was co-precipitated with β-catenin mRNA in H1299 cells , had abundant CpG islands  were collected from Tianjin Medical University General Hospital (TMUGH) with written consent. The metastatic status of patients was recorded on the basis of pathological and clinical examinations at the time of resection. The 40 LC samples were divided into two groups without or with LNM. The patients’ clinical features were summarized in http://www.kmplot.com) was used to verify the relevance of QKI mRNA level to overall survival of LC patients.An independent cohort of 1926 LC patients from the Kaplan Meier plotter  as previouslydescribed . IHC imaGAPDH mRNA was used as the internal control. The specific primers were synthesized by BGI (China) and listed in -ΔΔCt method.Total RNA was isolated using the TRIzol reagent  as the standard protocol. To determine the mRNA expressions of QKI transcripts, RT-PCR was performed as previously described , with M-Western blotting was carried out as previously described . The priQKI-5 cDNA sequence amplified by RT-PCR from the cDNA of H1299 cell line was cloned into pcDNA3.1 or pCMV-tag2b plasmid. The primers were listed in QKI-5 was subcloned into pMSCV-puro plasmid. The control (empty vector) or QKI-5-expressing retrovirus was constructed as previously described [Human escribed . The infescribed . Then, t2 at 37°C. To induce EMT, H1299 and A549 cells were starved in medium containing 0.1% FBS for 16 h before treatment with 5 ng/mL TGF-β1  for indicated hours. CHX  was used to treat H1299 cells for 0, 0.5, 1, 2, 3 h to interdict new β-catenin synthesis. To inhibit β-catenin degradation, H1299 cells were treated with proteasome inhibitor MG132 or GSK3β inhibitor SB415286  and harvested at 4 h for MG132 and 12 h or 24 h for SB415286.Human non-transformed bronchial epithelial cell line Beas2B, and LC cell lines H661, SPC-A1, SK-MES-1, H1299, H1373, H292 and A549 were all from the Chinese Infrastructure of Cell Line Resources. A549, H661, SPC-A1 and H292 cells were cultured in RPMI 1640 medium containing 10% FBS, and Beas2B, H1299, H1373 and SK-MES-1 cells were cultured in DMEM medium containing 10% FBS. All cell lines were maintained in an incubator containing 5% COThe small interfering RNA (siRNA) targeting β-catenin was synthesized by Gene Pharma (China), and the sequence was listed in 4/well) suspended in medium containing 1% FBS were seeded into the upper well of the transwell chamber pre-coated with 50 μl 1:4 diluted Matrigel  and allowed to invade towards the medium containing 10% FBS for 24 h. The cells that reached the lower surface were fixed with methanol and stained with 0.1% crystal violet. The cells were counted in 5 randomly selected microscopic fields (×400) from each chamber.Uniform artificial wounds were made at 2 d after transfection and the cells were cultured for another 24 h. Cell migration ability was represented by the wound gap distance in microscopic field (×40) at the time points of 0 and 24 h. For transwell invasion assay, at 24 h after transfection, the cells  or with wild type β-catenin 3’-UTR (β-cat) was structured as previously described . H1299-vRIP assay was performed using Magna RIP RNA-Binding Protein Immunoprecipitation Kit  according to manufacturer’s instruction. Flag antibody was used in RIP assays. The RNAs in immunoprecipitated complex and in the previously saved input fraction were extracted for further RT-PCR. Specific primers were applied for detecting the target mRNA .http://www.urogene.org/cgi-bin/methprimer/methprimer.cgi). The result was given at the default criteria .CpG island was predicted by the online Meth Primer tool (http://www.urogene.org/cgi-bin/methprimer/methprimer.cgi) [Genomic DNA was extracted from LC tissues and cell lines using a DNA extraction kit . After quantification, 2 μg of DNA was treated with sodium bisulfate as previously reported , and usemer.cgi)  and sequt test, Pearson correlation analysis, Kaplan-Meier analysis and log-rank test were used to analyze corresponding data in this study. Results were presented as the mean ± standard deviation (SD). Statistical significance was assigned at P<0.05 (*), P<0.01 (**) or P<0.001 (***). All the experiments of cell lines were performed at least three times with triplicate samples.Statistical analyses were performed using SPSS 21.0 software . One-way ANOVA test, Student