Oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate.

BACKGROUND: Safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers. METHODS/PRINCIPAL FINDINGS: We found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF(+) CD4(+) T cells and multifunctional IFNgamma(+)TNF(+) CD4(+) and CD8(+) T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin. CONCLUSIONS/SIGNIFICANCE: oAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64793756

Three Essays on Enhancing Clinical Trial Subject Recruitment Using Natural Language Processing and Text Mining

Patient recruitment and enrollment are critical factors for a successful clinical trial; however, recruitment tends to be the most common problem in most clinical trials. The success of a clinical trial depends on efficiently recruiting suitable patients to conduct the trial. Every clinical trial research has a protocol, which describes what will be done in the study and how it will be conducted. Also, the protocol ensures the safety of the trial subjects and the integrity of the data collected. The eligibility criteria section of clinical trial protocols is important because it specifies the necessary conditions that participants have to satisfy. Since clinical trial eligibility criteria are usually written in free text form, they are not computer interpretable. To automate the analysis of the eligibility criteria, it is therefore necessary to transform those criteria into a computer-interpretable format. Unstructured format of eligibility criteria additionally create search efficiency issues. Thus, searching and selecting appropriate clinical trials for a patient from relatively large number of available trials is a complex task. A few attempts have been made to automate the matching process between patients and clinical trials. However, those attempts have not fully integrated the entire matching process and have not exploited the state-of-the-art Natural Language Processing (NLP) techniques that may improve the matching performance. Given the importance of patient recruitment in clinical trial research, the objective of this research is to automate the matching process using NLP and text mining techniques and, thereby, improve the efficiency and effectiveness of the recruitment process. This dissertation research, which comprises three essays, investigates the issues of clinical trial subject recruitment using state-of-the-art NLP and text mining techniques. Essay 1: Building a Domain-Specific Lexicon for Clinical Trial Subject Eligibility Analysis Essay 2: Clustering Clinical Trials Using Semantic-Based Feature Expansion Essay 3: An Automatic Matching Process of Clinical Trial Subject Recruitment In essay1, I develop a domain-specific lexicon for n-gram Named Entity Recognition (NER) in the breast cancer domain. The domain-specific dictionary is used for selection and reduction of n-gram features in clustering in eassy2. The domain-specific dictionary was evaluated by comparing it with Systematized Nomenclature of Medicine--Clinical Terms (SNOMED CT). The results showed that it add significant number of new terms which is very useful in effective natural language processing In essay 2, I explore the clustering of similar clinical trials using the domain-specific lexicon and term expansion using synonym from the Unified Medical Language System (UMLS). I generate word n-gram features and modify the features with the domain-specific dictionary matching process. In order to resolve semantic ambiguity, a semantic-based feature expansion technique using UMLS is applied. A hierarchical agglomerative clustering algorithm is used to generate clinical trial clusters. The focus is on summarization of clinical trial information in order to enhance trial search efficiency. Finally, in essay 3, I investigate an automatic matching process of clinical trial clusters and patient medical records. The patient records collected from a prior study were used to test our approach. The patient records were pre-processed by tokenization and lemmatization. The pre-processed patient information were then further enhanced by matching with breast cancer custom dictionary described in essay 1 and semantic feature expansion using UMLS Metathesaurus. Finally, I matched the patient record with clinical trial clusters to select the best matched cluster(s) and then with trials within the clusters. The matching results were evaluated by internal expert as well as external medical expert

Advanced Methods for Entity Linking in the Life Sciences

The amount of knowledge increases rapidly due to the increasing number of available data sources. However, the autonomy of data sources and the resulting heterogeneity prevent comprehensive data analysis and applications. Data integration aims to overcome heterogeneity by unifying different data sources and enriching unstructured data. The enrichment of data consists of different subtasks, amongst other the annotation process. The annotation process links document phrases to terms of a standardized vocabulary. Annotated documents enable effective retrieval methods, comparability of different documents, and comprehensive data analysis, such as finding adversarial drug effects based on patient data. A vocabulary allows the comparability using standardized terms. An ontology can also represent a vocabulary, whereas concepts, relationships, and logical constraints additionally define an ontology. The annotation process is applicable in different domains. Nevertheless, there is a difference between generic and specialized domains according to the annotation process. This thesis emphasizes the differences between the domains and addresses the identified challenges. The majority of annotation approaches focuses on the evaluation of general domains, such as Wikipedia. This thesis evaluates the developed annotation approaches with case report forms that are medical documents for examining clinical trials. The natural language provides different challenges, such as similar meanings using different phrases. The proposed annotation method, AnnoMap, considers the fuzziness of natural language. A further challenge is the reuse of verified annotations. Existing annotations represent knowledge that can be reused for further annotation processes. AnnoMap consists of a reuse strategy that utilizes verified annotations to link new documents to appropriate concepts. Due to the broad spectrum of areas in the biomedical domain, different tools exist. The tools perform differently regarding a particular domain. This thesis proposes a combination approach to unify results from different tools. The method utilizes existing tool results to build a classification model that can classify new annotations as correct or incorrect. The results show that the reuse and the machine learning-based combination improve the annotation quality compared to existing approaches focussing on the biomedical domain. A further part of data integration is entity resolution to build unified knowledge bases from different data sources. A data source consists of a set of records characterized by attributes. The goal of entity resolution is to identify records representing the same real-world entity. Many methods focus on linking data sources consisting of records being characterized by attributes. Nevertheless, only a few methods can handle graph-structured knowledge bases or consider temporal aspects. The temporal aspects are essential to identify the same entities over different time intervals since these aspects underlie certain conditions. Moreover, records can be related to other records so that a small graph structure exists for each record. These small graphs can be linked to each other if they represent the same. This thesis proposes an entity resolution approach for census data consisting of person records for different time intervals. The approach also considers the graph structure of persons given by family relationships. For achieving qualitative results, current methods apply machine-learning techniques to classify record pairs as the same entity. The classification task used a model that is generated by training data. In this case, the training data is a set of record pairs that are labeled as a duplicate or not. Nevertheless, the generation of training data is a time-consuming task so that active learning techniques are relevant for reducing the number of training examples. The entity resolution method for temporal graph-structured data shows an improvement compared to previous collective entity resolution approaches. The developed active learning approach achieves comparable results to supervised learning methods and outperforms other limited budget active learning methods. Besides the entity resolution approach, the thesis introduces the concept of evolution operators for communities. These operators can express the dynamics of communities and individuals. For instance, we can formulate that two communities merged or split over time. Moreover, the operators allow observing the history of individuals. Overall, the presented annotation approaches generate qualitative annotations for medical forms. The annotations enable comprehensive analysis across different data sources as well as accurate queries. The proposed entity resolution approaches improve existing ones so that they contribute to the generation of qualitative knowledge graphs and data analysis tasks

Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study.

BackgroundHyperpolarized (HP) 13C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.MethodsSix patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13C-pyruvate, where pyruvate-to-lactate conversion rate (kPL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.ResultsWe observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean kPL value of 0.020 ± 0.006 (s-1) and 0.026 ± 0.000 (s-1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high kPL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of kPL from 0.026 at baseline to 0.015 (s-1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).ConclusionsHP 13C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative kPL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13C-pyruvate MRI in the setting of advanced prostate cancer

충수염 의증 청소년 및 젊은 성인에서 2-mSv CT와 기존 선량 CT의 민감도 및 특이도: LOCAT의 사후 하위그룹 분석

학위논문(박사)--서울대학교 대학원 :융합과학기술대학원 융합과학부,2019. 8. 이경호.Introduction: To explore heterogeneity across patient or hospital characteristics in the diagnostic sensitivity and specificity of 2-mSv CT relative to conventional-dose CT (CDCT) in adolescents and young adults with suspected appendicitis. Methods: We used the per-protocol analysis set of a large randomized controlled noninferiority trial conducted between Dec 2013, and Aug 2016, comparing 2-mSv CT and CDCT (typically 7 mSv). The data included 2,773 patients (median age [interquartile range], 28 [21–35] years) and 160 radiologists from 20 hospitals. We tested for heterogeneity in sensitivity and specificity for the diagnosis of appendicitis across predefined subgroups by patient sex, body size, clinical risk scores for appendicitis, time of CT examination (i.e., working hours [typically 08:00–17:00 of working days] vs. after hours), CT machines, radiologists experience, previous site experience in 2-mSv CT, and site practice volume. We drew forest plots and tested for additive or multiplicative treatment-by-subgroup interaction on sensitivity and specificity. Results: The 95% CIs for the between-group differences, particularly for sensitivity, were wide due to small sizes (< 200) for the subgroups of extreme body sizes, high clinical risk score for appendicitis, newer CT machines, hospital with prior experience in 2-mSv CT, and hospitals with small appendectomy volume. Otherwise, the 95% CIs in most subgroups contained the previously reported overall between-group differences as well as null hypothesis value (i.e., 0). There was no significant additive or multiplicative interaction for either sensitivity or specificity. Conclusions: We found no notable subgroup heterogeneity, which implies that 2-mSv CT can replace CDCT in diverse populations. Further studies are needed for the populations for which our subgroups were small.서론: 본 연구는 충수염 의증 청소년 및 젊은 성인에서 기존 CT와 비교하여 2-mSv CT의 진단 민감도 및 특이도에서 환자 또는 병원의 특성에 따른 이질성이 있는지를 탐색하는 연구임. 방법: 본 연구는 2013년 12월에서 2016년 8월 사이에 15–44세의 환자에서 2-mSv CT와 기존 선량 CT (일반적으로 7 mSv)를 비교한 대규모 비열등성 무작위배정 임상시험의 프로토콜 별 분석세트를 사용함. 본 연구에는 20개 병원에서 2,773명의 환자 (중앙값 연령 [사분위수 범위], 28 [21–35]세)가 포함되었으며, 160명의 판독의가 참여함. 환자의 성별, 신체 크기, 충수염에 대한 임상 위험 점수, CT 검사시간 (일과시간 [근무일 기준 오전 8시부터 오후5시] 또는 일과시간 이후), CT 장비, 판독의의 경험정도, 2-mSv CT에 대한 이전 경험 여부, 그리고 병원의 임상규모 등의 사전 정의된 하위 그룹에서 충수염 진단을 위한 민감도 및 특이도의 이질성을 테스트함. 두 군의 차이를 숲그림으로 제시하고, 민감도와 특이도에 대한 덧셈 및 곱셈 상호작용을 테스트함. 결과: 많이 날씬하거나 뚱뚱한 경우, 충수염 염증 반응 점수가 높은 경우, 최신 CT 기기를 사용한 경우, 2-mSV CT 의 이전 경험이 있는 병원, 그리고 충수절제술 규모가 작은 병원의 경우 등 특정 하위 그룹은 작은 크기 (< 200)로 인해 민감도에 대한 95 % 신뢰구간이 넓었음. 그 외, 대부분의 하위 그룹에서 그룹 간 차이에 대한 95 % 신뢰구간은 이전 보고된 전체 그룹 간 차이 및 귀무 가설 값 (즉, 0)을 포함하였음. 2-mSv CT 군과 기존 선량 CT 군 간에 민감도 및 특이도에서 덧셈 또는 곱셈 상호작용을 보이는 하위 그룹은 없었음. 결론: 충수염 의증 청소년과 젊은 성인에서 2-mSv CT와 기존 선량 CT 간에 민감도와 특이도에서 이질성을 보이는 하위그룹은 없었음. 이는 2-mSv CT가 다양한 집단에서 기존 선량 CT를 대체할 수 있음을 의미함. 다만, 본 연구에서 작은 크기를 가진 일부 하위 그룹에 대해서는 추가적인 연구가 필요함.INTRODUCTION 1 Motivations of LOCAT 1 Purposes of LOCAT 3 Motivations of Dissertation Research 4 Purposes of Dissertation Research 5 BACKGROUND 7 Epidemiology of Appendicitis and CT utilization 7 Imaging Utilization 7 Popularity of CT 8 CT Radiation 9 Radiation Dose Level 10 Typical Radiation Dose for Multi-purpose Abdomen CT 10 Typical Radiation Dose for Appendiceal CT 11 Low Doses Explored in Research Settings 12 Carcinogenic Risk Associated with CT Radiation 12 Controversy 13 ALARA Principle 14 Efficacy and Effectiveness of LDCT Compared to CDCT 15 Clinical Outcome 19 Diagnostic Performance 20 Inter-observer Agreement 21 Differentiation between Complicated vs. Uncomplicated Appendicitis 22 Image Quality 24 Visualization of the Appendix 24 Alternative Diagnoses 25 Step-wise Multimodal Diagnostic Approach Incorporating LDCT 27 Patient Subgroups Less Benefited from LDCT 27 Selective Utilization of LDCT 29 Additional Imaging Test(s) Following LDCT 30 Imaging Techniques for LDCT for Suspected Appendicitis 31 Intravenous Contrast Enhancement 31 Contrast-enhancement Phase 31 Enteric Contrast 32 Anatomical Coverage 32 Tube Current 33 Tube Potential 34 Iterative Reconstruction 34 Image Reconstruction Thickness 35 Coronal Reformation 35 Sliding-Slab Averaging Technique 36 Image Interpretation and Reporting for LDCT 37 Diagnostic Criteria for Appendicitis 37 Structured Reporting 38 Other Practical Issues in Implementing LDCT 39 Dedicated Protocol for Appendiceal CT 40 Education for Referring Physicians and Surgeons 41 Education for Radiologists 42 Dose Calibration and Monitoring 43 MATERIALS AND METHODS 47 Study Overview 47 Practice Setting 48 Pre-registration Procedures 48 Study Organization and Site Recruitment 49 Site Activation 50 Patients 51 Eligibility Criteria 54 Clinical Suspicion for Appendicitis 55 The Need for CT Examination 55 Generalizability 56 Representativeness of Study Sample 57 Withdrawal Criteria 58 Randomization 58 Index Test 59 CT Image Acquisition and Archiving 66 Radiation Doses 69 Record of Modulated Radiation Dose 71 Target Median DLP Values for the 2-mSv CT and CDCT groups 71 Calibration of Radiation Doses 72 Estimation of Carcinogenic Risk Associated with CT Examination 74 Image Interpretation 75 Radiologists and CT Reports 76 Radiologist Training 78 Considerations Regarding Technical Advantages over Previous Studies 79 Image Submission 80 Co-intervention 81 Additional Imaging 82 General Treatment Guidelines 82 Follow-up 84 Endpoints in LOCAT 85 Primary Endpoint 86 Secondary Endpoints 86 Considerations for NAR and APR 89 Changes in Endpoints 89 Reference Standards 91 Overview of Reference Standards 91 Definition of Acute Appendicitis 92 Mild or Early Acute Appendicitis 92 Appendiceal Diverticulitis 93 Cases of Delayed Appendectomy 93 Periappendicitis 93 Definition of Appendiceal Perforation 94 Reporting AEs 95 Definition of AE 96 Definition of SAE 97 AE Characteristics 97 Grade 98 Expected/Unexpected AEs 98 Attribution 98 Individual Symptoms vs. Single Diagnosis 99 Who Should Report AEs 99 How to Report AEs 99 Follow-up for AEs 100 Ethical Considerations 100 Ethics and Responsibility 100 Informed Consent Form 101 Data Security and Participant Confidentiality 101 Early Stopping Rules in LOCAT 101 Data Management 102 Case Report Forms 103 Monitoring Participant Accrual 103 Monitoring Data Quality 103 Data and Safety Monitoring Board 105 Statistical Analysis 105 Considerations for Primary Endpoint 105 Analysis Plans 107 Sample Size 108 Sample Size Considerations 108 Final Sample Size 110 Rationale for the Noninferiority Margin 111 Reported NARs Following Preoperative CT 111 Reported NARs in Patients Without Preoperative CT 112 Sample Size Considerations on APR 113 Subgroup Analyses for APR and NAR 114 Subgroup Analyses for Diagnostic Performance 116 RESULTS 119 Patient Characteristics 119 Overall Diagnostic Performance 123 Subgroups of Limited Comparison 123 Between-group Differences for Subgroups 123 Heterogeneity 131 DISCUSSION 132 CONCLUSION 139 REFERENCES 140 APPENDIX 164 Abstract in Korean 176Docto

Implementing multifactorial psychotherapy research in online virtual environments (IMPROVE-2): study protocol for a phase III trial of the MOST randomized component selection method for internet cognitive-behavioural therapy for depression.

BACKGROUND: Depression is a global health challenge. Although there are effective psychological and pharmaceutical interventions, our best treatments achieve remission rates less than 1/3 and limited sustained recovery. Underpinning this efficacy gap is limited understanding of how complex psychological interventions for depression work. Recent reviews have argued that the active ingredients of therapy need to be identified so that therapy can be made briefer, more potent, and to improve scalability. This in turn requires the use of rigorous study designs that test the presence or absence of individual therapeutic elements, rather than standard comparative randomised controlled trials. One such approach is the Multiphase Optimization Strategy, which uses efficient experimentation such as factorial designs to identify active factors in complex interventions. This approach has been successfully applied to behavioural health but not yet to mental health interventions. METHODS/DESIGN: A Phase III randomised, single-blind balanced fractional factorial trial, based in England and conducted on the internet, randomized at the level of the patient, will investigate the active ingredients of internet cognitive-behavioural therapy (CBT) for depression. Adults with depression (operationalized as PHQ-9 score ≥ 10), recruited directly from the internet and from an UK National Health Service Improving Access to Psychological Therapies service, will be randomized across seven experimental factors, each reflecting the presence versus absence of specific treatment components (activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, absorption, self-compassion training) using a 32-condition balanced fractional factorial design (2IV(7-2)). The primary outcome is symptoms of depression (PHQ-9) at 12 weeks. Secondary outcomes include symptoms of anxiety and process measures related to hypothesized mechanisms. DISCUSSION: Better understanding of the active ingredients of efficacious therapies, such as CBT, is necessary in order to improve and further disseminate these interventions. This study is the first application of a component selection experiment to psychological interventions in depression and will enable us to determine the main effect of each treatment component and its relative efficacy, and cast light on underlying mechanisms, so that we can systematically enhance internet CBT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24117387 . Registered 26 August 2014.Funding for this trial is provided by grants from the Cornwall NHS Foundation Trust and South West Peninsula Academic Health Research Network to EW. LC is supported by United States National Institutes of Health grants P50DA039838, P01CA180945, R01DK097364, and R01AA022931

Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention-MACUSTAR.

BACKGROUND: There is an unmet need for treatment options in intermediate age-related macular degeneration (iAMD). However, for any new interventions to be tested in clinical trials, novel currently unavailable clinical endpoints need to be developed. Thus, the MACUSTAR study aims to develop and evaluate functional, structural, and patient-reported candidate endpoints for use in future iAMD trials. METHODS: The protocol describes a low-interventional clinical multicenter study employing a novel two-part design. The cross-sectional part (total duration, 1 month) and the longitudinal part (total duration, 36 months) include participants with iAMD and control groups with early/late/no AMD. The cross-sectional part's primary objective is a technical evaluation of functional, structural, and patient-reported candidate outcomes. The longitudinal part's primary objective is to assess the prognostic power of changes in functional, structural, and patient-reported outcomes for progression from iAMD to late AMD. All data will be used to support a biomarker qualification procedure by regulatory authorities. DISCUSSION: The MACUSTAR study characterizes and evaluates much needed novel functional, structural, and patient-reported endpoints for future clinical trials in iAMD and will improve our understanding of the natural history and prognostic markers of this condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017

Treatment Courts and Court-Affiliated Diversion Projects for Prostitution in the United States

In February of 2009, staff of the Chicago Coalition for the Homeless began a dialogue with the Honorable Paul P. Biebel, Presiding Judge of Cook County Criminal Courts, regarding the possibility of a new problem-solving court specializing in prostitution offenses. For our own edification, we searched for other court models around the country with this same focus. We found several; however, there was no centralized source of information. There was also a lack of shared information among those responsible for coordinating these court projects. In fact, few of these court teams were aware of the other courts in operation. We found more and more court models randomly via keyword searches on the Internet or word of mouth. Those that we contacted regarding their court models were eager and enthusiastic about their models, willing to openly share any information requested, and excited about the prospect of new models and connecting with other existing courts and their associated programs.As we moved further into developing and preparing for the WINGS Project, the newly formed felony prostitution court in Cook County, Illinois, we felt that it would be highly beneficial to begin sharing the knowledge, best practices, and contact information among the courts throughout the country. We wanted to create a tool that facilitated communication and learning between all of the court teams. The information regarding these courts was invaluable in the creation of the WINGS Project, and we hope it can be as useful for other specialty courts for prostitution offenses around the country.The authors of this report have not physically observed any of the court or diversion projects described in this report other than the WINGS Project/Feathers and the Maywood court calls. The information presented about each project is based on countless hours of phone interviews and email communication, as well as any online articles or reports; therefore, the information presented is not completely neutral, and any subjective information or views expressed within those sections do not necessarily reflect the views of the authors.The court and diversion projects in this report are by no means meant to be an exhaustive list, but rather only what we have been able to find through extensive research to date. This report is, and may always be, a work in progress. Our hope is that this report will also help us gain awareness of other projects and even spur other communities to develop similar projects. The sharing of this tool should lead to even greater sharing, ever-improving models, and a much more comprehensive base of knowledge on the subject of effective criminal justice-based models that divert individuals with prostitution offenses away from prison and into desperately needed community-based services