University of Arkansas for Medical Sciences

INTRODUCTION: Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. METHODS: Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. RESULTS: The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. CONCLUSION: We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

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PROBLEM/CONDITION: Autism spectrum disorder (ASD). PERIOD COVERED: 2014. DESCRIPTION OF SYSTEM: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that provides estimates of the prevalence of autism spectrum disorder (ASD) among children aged 8 years whose parents or guardians reside within 11 ADDM sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). ADDM surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by professional service providers in the community. Staff completing record review and abstraction receive extensive training and supervision and are evaluated according to strict reliability standards to certify effective initial training, identify ongoing training needs, and ensure adherence to the prescribed methodology. Record review and abstraction occurs in a variety of data sources ranging from general pediatric health clinics to specialized programs serving children with developmental disabilities. In addition, most of the ADDM sites also review records for children who have received special education services in public schools. In the second phase of the study, all abstracted information is reviewed systematically by experienced clinicians to determine ASD case status. A child is considered to meet the surveillance case definition for ASD if he or she displays behaviors, as described on one or more comprehensive evaluations completed by community-based professional providers, consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for autistic disorder; pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism); or Asperger disorder. This report provides updated ASD prevalence estimates for children aged 8 years during the 2014 surveillance year, on the basis of DSM-IV-TR criteria, and describes characteristics of the population of children with ASD. In 2013, the American Psychiatric Association published the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which made considerable changes to ASD diagnostic criteria. The change in ASD diagnostic criteria might influence ADDM ASD prevalence estimates; therefore, most (85%) of the records used to determine prevalence estimates based on DSM-IV-TR criteria underwent additional review under a newly operationalized surveillance case definition for ASD consistent with the DSM-5 diagnostic criteria. Children meeting this new surveillance case definition could qualify on the basis of one or both of the following criteria, as documented in abstracted comprehensive evaluations: 1) behaviors consistent with the DSM-5 diagnostic features; and/or 2) an ASD diagnosis, whether based on DSM-IV-TR or DSM-5 diagnostic criteria. Stratified comparisons of the number of children meeting either of these two case definitions also are reported. RESULTS: For 2014, the overall prevalence of ASD among the 11 ADDM sites was 16.8 per 1,000 (one in 59) children aged 8 years. Overall ASD prevalence estimates varied among sites, from 13.1-29.3 per 1,000 children aged 8 years. ASD prevalence estimates also varied by sex and race/ethnicity. Males were four times more likely than females to be identified with ASD. Prevalence estimates were higher for non-Hispanic white (henceforth, white) children compared with non-Hispanic black (henceforth, black) children, and both groups were more likely to be identified with ASD compared with Hispanic children. Among the nine sites with sufficient data on intellectual ability, 31% of children with ASD were classified in the range of intellectual disability (intelligence quotient [IQ] <70), 25% were in the borderline range (IQ 71-85), and 44% had IQ scores in the average to above average range (i.e., IQ >85). The distribution of intellectual ability varied by sex and race/ethnicity. Although mention of developmental concerns by age 36 months was documented for 85% of children with ASD, only 42% had a comprehensive evaluation on record by age 36 months. The median age of earliest known ASD diagnosis was 52 months and did not differ significantly by sex or race/ethnicity. For the targeted comparison of DSM-IV-TR and DSM-5 results, the number and characteristics of children meeting the newly operationalized DSM-5 case definition for ASD were similar to those meeting the DSM-IV-TR case definition, with DSM-IV-TR case counts exceeding DSM-5 counts by less than 5% and approximately 86% overlap between the two case definitions (kappa = 0.85). INTERPRETATION: Findings from the ADDM Network, on the basis of 2014 data reported from 11 sites, provide updated population-based estimates of the prevalence of ASD among children aged 8 years in multiple communities in the United States. The overall ASD prevalence estimate of 16.8 per 1,000 children aged 8 years in 2014 is higher than previously reported estimates from the ADDM Network. Because the ADDM sites do not provide a representative sample of the entire United States, the combined prevalence estimates presented in this report cannot be generalized to all children aged 8 years in the United States. Consistent with reports from previous ADDM surveillance years, findings from 2014 were marked by variation in ASD prevalence when stratified by geographic area, sex, and level of intellectual ability. Differences in prevalence estimates between black and white children have diminished in most sites, but remained notable for Hispanic children. For 2014, results from application of the DSM-IV-TR and DSM-5 case definitions were similar, overall and when stratified by sex, race/ethnicity, DSM-IV-TR diagnostic subtype, or level of intellectual ability. PUBLIC HEALTH ACTION: Beginning with surveillance year 2016, the DSM-5 case definition will serve as the basis for ADDM estimates of ASD prevalence in future surveillance reports. Although the DSM-IV-TR case definition will eventually be phased out, it will be applied in a limited geographic area to offer additional data for comparison. Future analyses will examine trends in the continued use of DSM-IV-TR diagnoses, such as autistic disorder, PDD-NOS, and Asperger disorder in health and education records, documentation of symptoms consistent with DSM-5 terminology, and how these trends might influence estimates of ASD prevalence over time. The latest findings from the ADDM Network provide evidence that the prevalence of ASD is higher than previously reported estimates and continues to vary among certain racial/ethnic groups and communities. With prevalence of ASD ranging from 13.1 to 29.3 per 1,000 children aged 8 years in different communities throughout the United States, the need for behavioral, educational, residential, and occupational services remains high, as does the need for increased research on both genetic and nongenetic risk factors for ASD.

BACKGROUND: Identifying, developing, and testing implementation strategies are important goals of implementation science. However, these efforts have been complicated by the use of inconsistent language and inadequate descriptions of implementation strategies in the literature. The Expert Recommendations for Implementing Change (ERIC) study aimed to refine a published compilation of implementation strategy terms and definitions by systematically gathering input from a wide range of stakeholders with expertise in implementation science and clinical practice. METHODS: Purposive sampling was used to recruit a panel of experts in implementation and clinical practice who engaged in three rounds of a modified Delphi process to generate consensus on implementation strategies and definitions. The first and second rounds involved Web-based surveys soliciting comments on implementation strategy terms and definitions. After each round, iterative refinements were made based upon participant feedback. The third round involved a live polling and consensus process via a Web-based platform and conference call. RESULTS: Participants identified substantial concerns with 31% of the terms and/or definitions and suggested five additional strategies. Seventy-five percent of definitions from the originally published compilation of strategies were retained after voting. Ultimately, the expert panel reached consensus on a final compilation of 73 implementation strategies. CONCLUSIONS: This research advances the field by improving the conceptual clarity, relevance, and comprehensiveness of implementation strategies that can be used in isolation or combination in implementation research and practice. Future phases of ERIC will focus on developing conceptually distinct categories of strategies as well as ratings for each strategy's importance and feasibility. Next, the expert panel will recommend multifaceted strategies for hypothetical yet real-world scenarios that vary by sites' endorsement of evidence-based programs and practices and the strength of contextual supports that surround the effort.

OBJECTIVES: This study proposes methods for blending design components of clinical effectiveness and implementation research. Such blending can provide benefits over pursuing these lines of research independently; for example, more rapid translational gains, more effective implementation strategies, and more useful information for decision makers. This study proposes a "hybrid effectiveness-implementation" typology, describes a rationale for their use, outlines the design decisions that must be faced, and provides several real-world examples. RESULTS: An effectiveness-implementation hybrid design is one that takes a dual focus a priori in assessing clinical effectiveness and implementation. We propose 3 hybrid types: (1) testing effects of a clinical intervention on relevant outcomes while observing and gathering information on implementation; (2) dual testing of clinical and implementation interventions/strategies; and (3) testing of an implementation strategy while observing and gathering information on the clinical intervention's impact on relevant outcomes. CONCLUSIONS: The hybrid typology proposed herein must be considered a construct still in evolution. Although traditional clinical effectiveness and implementation trials are likely to remain the most common approach to moving a clinical intervention through from efficacy research to public health impact, judicious use of the proposed hybrid designs could speed the translation of research findings into routine practice.

BACKGROUND: The main problem in many model-building situations is to choose from a large set of covariates those that should be included in the "best" model. A decision to keep a variable in the model might be based on the clinical or statistical significance. There are several variable selection algorithms in existence. Those methods are mechanical and as such carry some limitations. Hosmer and Lemeshow describe a purposeful selection of covariates within which an analyst makes a variable selection decision at each step of the modeling process. METHODS: In this paper we introduce an algorithm which automates that process. We conduct a simulation study to compare the performance of this algorithm with three well documented variable selection procedures in SAS PROC LOGISTIC: FORWARD, BACKWARD, and STEPWISE. RESULTS: We show that the advantage of this approach is when the analyst is interested in risk factor modeling and not just prediction. In addition to significant covariates, this variable selection procedure has the capability of retaining important confounding variables, resulting potentially in a slightly richer model. Application of the macro is further illustrated with the Hosmer and Lemeshow Worchester Heart Attack Study (WHAS) data. CONCLUSION: If an analyst is in need of an algorithm that will help guide the retention of significant covariates as well as confounding ones they should consider this macro as an alternative tool.

PROBLEM/CONDITION: Autism spectrum disorder (ASD). PERIOD COVERED: 2016. DESCRIPTION OF SYSTEM: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance program that provides estimates of the prevalence of ASD among children aged 8 years whose parents or guardians live in 11 ADDM Network sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). Surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by medical and educational service providers in the community. In the second phase, experienced clinicians who systematically review all abstracted information determine ASD case status. The case definition is based on ASD criteria described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. RESULTS: For 2016, across all 11 sites, ASD prevalence was 18.5 per 1,000 (one in 54) children aged 8 years, and ASD was 4.3 times as prevalent among boys as among girls. ASD prevalence varied by site, ranging from 13.1 (Colorado) to 31.4 (New Jersey). Prevalence estimates were approximately identical for non-Hispanic white (white), non-Hispanic black (black), and Asian/Pacific Islander children (18.5, 18.3, and 17.9, respectively) but lower for Hispanic children (15.4). Among children with ASD for whom data on intellectual or cognitive functioning were available, 33% were classified as having intellectual disability (intelligence quotient [IQ] ≤70); this percentage was higher among girls than boys (39% versus 32%) and among black and Hispanic than white children (47%, 36%, and 27%, respectively) [corrected]. Black children with ASD were less likely to have a first evaluation by age 36 months than were white children with ASD (40% versus 45%). The overall median age at earliest known ASD diagnosis (51 months) was similar by sex and racial and ethnic groups; however, black children with IQ ≤70 had a later median age at ASD diagnosis than white children with IQ ≤70 (48 months versus 42 months). INTERPRETATION: The prevalence of ASD varied considerably across sites and was higher than previous estimates since 2014. Although no overall difference in ASD prevalence between black and white children aged 8 years was observed, the disparities for black children persisted in early evaluation and diagnosis of ASD. Hispanic children also continue to be identified as having ASD less frequently than white or black children. PUBLIC HEALTH ACTION: These findings highlight the variability in the evaluation and detection of ASD across communities and between sociodemographic groups. Continued efforts are needed for early and equitable identification of ASD and timely enrollment in services.

BACKGROUND: Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer. METHODS: We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. RESULTS: Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. CONCLUSIONS: The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients.This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation.This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 [1].The objective of these

Problem/Condition: Autism spectrum disorder (ASD). Period Covered: 2020. Description of System: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance program that provides estimates of the prevalence of ASD among children aged 8 years. In 2020, there were 11 ADDM Network sites across the United States (Arizona, Arkansas, California, Georgia, Maryland, Minnesota, Missouri, New Jersey, Tennessee, Utah, and Wisconsin). To ascertain ASD among children aged 8 years, ADDM Network staff review and abstract developmental evaluations and records from community medical and educational service providers. A child met the case definition if their record documented 1) an ASD diagnostic statement in an evaluation, 2) a classification of ASD in special education, or 3) an ASD International Classification of Diseases (ICD) code. Results: For 2020, across all 11 ADDM sites, ASD prevalence per 1,000 children aged 8 years ranged from 23.1 in Maryland to 44.9 in California. The overall ASD prevalence was 27.6 per 1,000 (one in 36) children aged 8 years and was 3.8 times as prevalent among boys as among girls (43.0 versus 11.4). Overall, ASD prevalence was lower among non-Hispanic White children (24.3) and children of two or more races (22.9) than among non-Hispanic Black or African American (Black), Hispanic, and non-Hispanic Asian or Pacific Islander (A/PI) children (29.3, 31.6, and 33.4 respectively). ASD prevalence among non-Hispanic American Indian or Alaska Native (AI/AN) children (26.5) was similar to that of other racial and ethnic groups. ASD prevalence was associated with lower household income at three sites, with no association at the other sites.Across sites, the ASD prevalence per 1,000 children aged 8 years based exclusively on documented ASD diagnostic statements was 20.6 (range = 17.1 in Wisconsin to 35.4 in California). Of the 6,245 children who met the ASD case definition, 74.7% had a documented diagnostic statement of ASD, 65.2% had a documented ASD special education classification, 71.6% had a documented ASD ICD code, and 37.4% had all three types of ASD indicators. The median age of earliest known ASD diagnosis was 49 months and ranged from 36 months in California to 59 months in Minnesota.Among the 4,165 (66.7%) children with ASD with information on cognitive ability, 37.9% were classified as having an intellectual disability. Intellectual disability was present among 50.8% of Black, 41.5% of A/PI, 37.8% of two or more races, 34.9% of Hispanic, 34.8% of AI/AN, and 31.8% of White children with ASD. Overall, children with intellectual disability had earlier median ages of ASD diagnosis (43 months) than those without intellectual disability (53 months). Interpretation: For 2020, one in 36 children aged 8 years (approximately 4% of boys and 1% of girls) was estimated to have ASD. These estimates are higher than previous ADDM Network estimates during 2000-2018. For the first time among children aged 8 years, the prevalence of ASD was lower among White children than among other racial and ethnic groups, reversing the direction of racial and ethnic differences in ASD prevalence observed in the past. Black children with ASD were still more likely than White children with ASD to have a co-occurring intellectual disability. Public Health Action: The continued increase among children identified with ASD, particularly among non-White children and girls, highlights the need for enhanced infrastructure to provide equitable diagnostic, treatment, and support services for all children with ASD. Similar to previous reporting periods, findings varied considerably across network sites, indicating the need for additional research to understand the nature of such differences and potentially apply successful identification strategies across states.

New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20-25% or greater lifetime risk of breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin disease. There are several risk subgroups for which the available data are insufficient to recommend for or against screening, including women with a personal history of breast cancer, carcinoma in situ, atypical hyperplasia, and extremely dense breasts on mammography. Diagnostic uses of MRI were not considered to be within the scope of this review.

BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy.

Before publication of the original version of this report in 1987, practitioners of bone histomorphometry communicated with each other in a variety of arcane languages, which in general were unintelligible to those outside the field. The need for standardization of nomenclature had been recognized for many years,1 during which there had been much talk but no action. To satisfy this need, B Lawrence Riggs (ASBMR President, 1985 to 1986) asked A Michael Parfitt to convene an ASBMR committee to develop a new and unified system of terminology, suitable for adoption by the Journal of Bone and Mineral Research (JBMR) as part of its Instructions to Authors. The resulting recommendations were published in 19872 and were quickly adopted not only by JBMR but also by all respected journals in the bone field. The recommendations improved markedly the ability of histomorphometrists to communicate with each other and with nonhistomorphometrists, leading to a broader understanding and appreciation of histomorphometric data. In 2012, 25 years after the development of the standardized nomenclature system, Thomas L Clemens (Editor in Chief of JBMR) felt that it was time to revise and update the recommendations. The original committee was reconvened by David W Dempster, who appointed one new member, Juliet E Compston. The original document was circulated to the committee members and was extensively revised according to their current recommendations. The key revisions include omission of terminology used before 1987, recommendations regarding the parameters and technical information that should be included in all histomorphometry articles, recommendations on how to handle dynamic parameters of bone formation in settings of low bone turnover, and updating of references. It is generally agreed that a bone is an individual organ of the skeletal system, but the term "bone" has at least three meanings. The first is mineralized bone matrix excluding osteoid; this usage conforms rigorously to the definition of bone as a hard tissue. Osteoid is bone matrix that will be (but is not yet) mineralized, and is sometimes referred to as pre-bone. The second meaning of "bone," and the one we have adopted, is bone matrix, whether mineralized or not, ie, including both mineralized bone and osteoid. The third meaning of "bone" is a tissue including bone marrow and other soft tissue, as well as bone as just defined. We refer to the combination of bone and associated soft tissue or marrow as "bone tissue." "Tissue" is defined3 as "an aggregation of similarly specialized cells united in the performance of a particular function." In this sense, bone, bone marrow, and the contents of osteonal canals are certainly not the same tissue, but in a more general sense, most textbooks of histology recognize only four fundamental tissues—epithelium, nerve, muscle, and connective tissue4—of which the last-named includes bone and all its accompanying nonmineralized tissue. In current clinical and radiologic parlance, "trabecular" and "cortical" refer to contrasting structural types of bone. But "trabecular" does not appear in any standard textbook of anatomy or histology as a name for a type of bone; rather, "spongy" or "cancellous" is used. "Spongiosa" (primary or secondary) is best restricted to the stages of endochondral ossification; "cancellous" is most commonly used in textbooks4, 5 and is the term we have chosen. We retain the noun "trabecula" and its associated adjective "trabecular" to refer to an individual structural element of cancellous bone, in accordance with current practice in histology,4 pathology,6 and biomechanics.7 Etymologically, a trabecula is a beam or rod, and in young people plates rather than rods are the predominant structural elements, both in the spine8 and in the ilium,9 but no convenient alternative is available. The size, shape, and orientation of trabeculae (as just defined) vary considerably between different types of cancellous bone.9, 10 "Density" is a frequent source of confusion in discussions about bone. We propose that the term should be restricted as far as possible to its primary meaning in physics of mass per unit volume,11, 12 with a subsidiary meaning analogous to population density, which is applied mainly to cells. This precludes the use of "density" in its stereologic sense, as will be discussed later. Corresponding to the definitions given earlier, the volume to which mass is referred can be of mineralized bone, bone, bone tissue (cortical or cancellous), or a whole bone. Mineralized bone density is slightly less than true bone density, which excludes the volume of osteocyte lacunae and canaliculi.11 This volume is small and generally ignored; lacunar volume can be readily measured,13 but canalicular volume is inaccessible to light microscopy. Bone density reflects the volumetric proportion of osteoid; bone matrix volume, excluding lacunar and canalicular volume, has been referred to as absolute bone volume.14 Bone tissue density reflects the volumetric proportion of soft tissue, or porosity. Whole bone density, often referred to as apparent bone density, reflects the volumetric proportions of cortical bone tissue, cancellous bone tissue, and diaphyseal marrow within a bone, the organ volume of which is usually measured by Archimedes' principle.15 "Osteoblast" is defined differently in the clinical and experimental literature. In young, rapidly growing small animals, most bone surfaces are undergoing either resorption or formation and virtually all cells on the surface are either osteoclasts or osteoblasts,16 but in the adult human, most bone surfaces are quiescent with respect to bone remodeling. We refer to the flat cells that cover quiescent internal (nonperiosteal) bone surfaces as lining cells and restrict the term "osteoblast" to cells that are making bone matrix currently or with only temporary interruption, rather than including all surface cells that are not osteoclasts.16 Lining cells are of osteoblast lineage and are thought to have osteogenic potential.17 The term "osteoclast" is restricted to bone-resorbing cells containing lysosomes and tartrate-resistant acid phosphatase; they are usually multinucleated, although some osteoclast profiles may have only one or no nucleus. Criteria for identification of osteoblasts and osteoclasts, whether morphologic or histochemical,18, 19 should always be stated or referenced. A two-dimensional histological section displays profiles of three-dimensional structures. Four types of primary measurement can be made on these profiles—area, length (usually of a perimeter or boundary), distance between points or between lines, and number.20 Some histomorphometrists report all results only in these two-dimensional terms because the assumptions needed for extrapolation to three dimensions may be difficult to justify and because the diagnostic significance of the measurements or the statistical significance of an experimental result are not affected. For these limited objectives, this is a reasonable view, but bone cannot be fully understood unless conceived in three-dimensional terms. In every other branch of science that uses microscopy as an investigative tool, the ultimate goal is to understand three-dimensional reality by the application of stereology, which is the relevant mathematical discipline.20-22 We believe that this also should be the goal of bone histomorphometry. Accurate three-dimensional data are necessary for proper comparison between species, between bones, and between different types of bone, for input into finite element models of bone strength, for realistic estimation of radiation burdens, and for many aspects of bone physiology, such as the calculation of diffusion distances and the measurement of individual cell work. But as a practical matter, it is unrealistic to insist on universal adoption of a three-dimensional format. All stereologic theorems require that sampling be random and unbiased, a condition only rarely fulfilled in bone histomorphometry; the closest feasible approach is to rotate the cylindrical bone sample randomly around its longitudinal axis before embedding.20, 23 In the past, the use of a hemispherical grid20-22 in the ocular lens was a convenient way of ensuring randomness of test line orientation, but even this cannot compensate for sampling bias introduced at an earlier stage. With the exception of the conversion of area fractions to volume fractions, most stereologic theorems also require that the structure be isotropic, meaning that a perpendicular to any element of surface has an equal likelihood of pointing in any direction in space.20, 24 Although not true for all cancellous bone, in the ilium there is only moderate deviation from isotropy, and stereologic theorems may be used with acceptable error.24, 25 But it is more accurate to apply the theory of vertical sections; a cycloid test grid is required, which is incompatible with the use of a digitizer,23, 26 but there is no other way of obtaining truly unbiased estimates. Because Haversian canals generally do not deviate from the long axis by more than 10°, stereologic problems in diaphyseal cortical bone are minimal, but investigation of the correct stereologic approach to iliac cortical bone has not been done. Accordingly, we recommend that everyone reporting histomorphometric data should select one of two options: either present all results strictly and consistently in two dimensions, using the terms perimeter (for length), area, and width (for distance), or (as favored by the committee) present only the corresponding three-dimensional results using the terms surface, volume, and thickness; with the latter option, an explanation is needed for each type of measurement of exactly how it was derived from the primary two-dimensional measurement, as described later. A mixture of two- and three-dimensional terms should not be used in the same article. The only exception is number, the fourth type of primary measurement, for which there is no convenient way of extrapolating to three dimensions without making assumptions concerning the three-dimensional shape of the objects counted.21, 22 Direct enumeration of number in three dimensions is possible if the same object can be identified in serial sections of known thickness and separation,27 but this method has not yet been applied to bone. Topological properties such as connectivity also cannot be determined from two-dimensional sections.28 The original committee chose not to adopt the terminology of the International Society of Stereology, as was suggested at the First International Workshop on Bone Morphometry.29 Stereologists use the term "density" in a very general sense to identify any measurement referred to some defined containing volume,21, 22 so that fractional volume is "volume density" (Vv) and surface area per unit volume is "surface density" (Sv). Although the unification of scientific terminology is desirable in the long term, the practical disadvantage of using "density" in two different senses outweighs the theoretical advantage. Nevertheless, all investigators wishing to remain at the cutting edge of bone histomorphometry will need to be thoroughly familiar with the terminologic conventions of stereology because many important methodologic articles applicable to bone are published in the Journal of Microscopy, which is the official journal of the International Society of Stereology.26-28 Primary two-dimensional measurements of perimeter, area, and number are indices of the amount of tissue examined and can be compared between subjects only when related to a common referent, which will be some clearly defined area or perimeter within the section. Absolute perimeter length and absolute area in two dimensions have no corresponding absolute surface area and absolute volume in three dimensions, but it is convenient to refer to perimeters as surfaces and to areas as volumes if the appropriate referent is clear from the context. Primary two-dimensional measurements of width (and corresponding three-dimensional thicknesses) and mean profile areas of individual structures have meaning in isolation and are the only type that do not require a referent. Different referents serve different purposes and lead to different interpretations, so that use of multiple referents is unavoidable, and it is important to clearly distinguish between them.30 Commonly used referents include tissue volume (TV), bone volume (BV), bone surface (BS), and osteoid surface (OS) and their corresponding two-dimensional areas or perimeters. With explicit identification of the referent, the use of "relative" as a qualifying term becomes redundant. The volume of the cylindrical biopsy core is not commonly used as a referent at present but is needed for comparison with physical methods of measuring bone density,31 for comparing the absolute amounts of cortical and cancellous bone lost because of aging or disease,31 for determining the contributions of different types of bone and different surfaces to various histological indices, such as amount of osteoid and surface extent of osteoblasts,32 and for examining in detail the relationships between histological and biochemical indices of whole-body bone remodeling.32 Use of the core volume (CV) as a referent provides the closest approach possible from an iliac biopsy to the in vivo level of organization corresponding to bone as an organ. An intact, full-thickness transiliac biopsy can be regarded as representative of the entire bone18, 33 because the length of the cylindrical biopsy core perpendicular to the external surface depends mainly on the width of the iliac bone at the site of sampling. Cortical thickness can be measured with a vertical biopsy through the iliac crest,5 but the proportions of cortical and cancellous tissue in the bone cannot be measured. However, with either type of biopsy, the results can be weighted by the proportions of cortical and cancellous bone tissue in the entire skeleton.34 The same principle can be applied to rib biopsies and to long bone cross sections by using the whole area enclosed by the periosteum as the referent. The recommended individual terms are listed in Table 1 in alphabetical order of their abbreviations or symbols. Several general comments are in order. First, like a dictionary, the lexicon is intended to be consulted, rather than memorized. Second, the use of abbreviations is always discretionary, never compulsory. Although designed mainly to save time or space, there is a more subtle reason for abbreviations, as for other symbols. Words frequently carry unwanted implications from their use in other contexts, but confusion is less likely with symbols that can be approached with fewer preconceptions.1 Nevertheless, our purpose is not to encourage or discourage the use of abbreviations and symbols but to ensure that the same ones are used by everybody. To this end, we have made the lexicon comprehensive to anticipate future needs and forestall the introduction of new abbreviations with different meanings. We have included metals frequently identified in bone (with their usual elemental abbreviations) and terms commonly used in quantitative microscopy and stereology, as well as terms for all the major structural features of bone and of bones and for some important concepts of bone physiology. Terms with unfamiliar meanings are explained and defined in relation to their use. With one exception, the abbreviations and symbols in Table 1 consist of only two letters; "BMU" (basic multicellular unit) is retained because it is important and widely used and lacks a suitable alternative. The most commonly used descriptive terms are given a single capital letter. Other terms have an additional lowercase letter, chosen in many cases to emphasize the second or later syllable and usually avoiding the second letter of the word abbreviated by the single capital letter. Single lowercase letters are used for terms that are in some sense related to time, for the primary data of classical grid counting (hit and intersection), and for n in its usual statistical sense. When used in combination, double-letter abbreviations should be demarcated by a period; in the absence of periods, each letter is to be construed as an individual abbreviation. In this way, any combination of abbreviations can be unambiguously deciphered without having to determine which terms are included in the lexicon. Bone histomorphometry can be applied to many types of material, but the most common are sections of cylindrical biopsy samples of iliac bone obtained from human subjects and sections of long bones obtained from experimental animals. For orientation, we first present the terminology for describing these sections. "Core" (C) refers to the entire biopsy specimen (Fig. 1). For transiliac biopsies, the distance between external (Ex) and internal (In) periosteum is termed "width" (Wi) because it is related to the thickness of the iliac bone at the biopsy site; for vertical biopsies through the iliac crest, the term "length" (Le) is more appropriate. Core width is subdivided into cortical (Ct) widths and cancellous (Cn) width; for transiliac biopsies, measurements on the two cortices (including their width) are usually pooled, but it is possible to keep track of their identity and examine them separately. In this case, the two cortices are generally distinguished by their width (thick versus thin). Identification of the inner and outer cortex would require that one be marked in some way (eg, by ink or cotton thread) at the time of the biopsy, but this is seldom done. The outer cortex generally has more attached fibrous and muscle tissue than the inner cortex. The other dimension of the core is referred to as "diameter" (Dm), although only sections through the central axis of the cylinder have the same diameter as the trephine; the more accurate term "chord length" is too cumbersome. If the axis of the transiliac core is oblique to the plane of the ilium, its dimensions are apparently changed (Fig. It is convenient to core diameter as mean length" and of because true for cortical and cancellous width for are given by the relationships between length and area in the to of representative bone biopsies from different transiliac cortex on vertical on by transiliac biopsy from and with of sections through cylindrical biopsy core of of perpendicular on oblique on core width; core cortical width; cancellous to core area cortical area cancellous area the inner and outer periosteum do not from and their mean length is used for these relationships remain true for the oblique section because the areas enclosed by the and are the relationships can be used to and without measuring the of For long bone cross sections (Fig. bone diameter is similarly subdivided into two cortical widths and either cancellous diameter for cross or marrow diameter for diaphyseal cross sections. The relationships between these and bone area, cortical area, and cancellous or marrow area depends on the of the cross section. For such measurements may be needed at multiple in relation to the in vivo For both iliac and long bone it is necessary for purposes to recognize a between cortical and cancellous bone tissue and in and This is not in or because methods of its are not yet fully A has been used to this in quantitative This may be applicable to iliac bone biopsy but this has not yet been For all bones, all surfaces in with bone marrow are referred to as and are subdivided into cancellous bone surface and the latter is the inner of the cortex. between these is to unless made in accordance with some and will also on whether the is measured separately. surfaces not in with bone marrow are generally referred to as cortical with as the cortical surface can also be referred to as the Haversian or osteonal of cross sections through the of a long bone; is on the and diaphyseal is on the For the cancellous bone of the is not bone cortical width; cancellous marrow The standard and applicable method for reporting all data should be that the of to as well as to the and are used only as and are used only as described refers to the structure on which the measurement was whether this was a particular surface or a particular type of tissue. of the commonly used have been defined many are by using the lexicon 1). If measurements are restricted to some of a such as the outer of a or the central of cancellous the same can be but the appropriate should be made in the of For measurements made on the entire the source is identified as it will not be necessary to the source each time a particular is referred only one source is used in an it need only be If are their can be used as for of results in or and in most cases will need to be only if measurements from are discussed such that confusion between them is For some such as only one source is possible and its is redundant. The three and the two are the key needed to from one referent to is to in stereologic terminology, and and are to in stereologic are derived from the corresponding two-dimensional and either by which is correct for or by which has been determined for human iliac cancellous The with so that the always be stated and and to in stereologic terminology and are with the corresponding and For some a of the bone surface is needed as a referent surface and surface are often related to osteoid surface usually and it can be to osteoclasts to the mineralized surface as an alternative to the more usual referents bone surface and surface indices of bone formation can be related to the osteoblast surface or to the number of osteoblast profiles as well as to osteoid surface or bone it may be appropriate to use the between mineralized bone and or bone as a referent for the length of or of because the is these features are In many as when only one referent is used for each measurement, the referent need only be and not each time the measurement is If more than one referent is measurements with the same referent can be to are listed with abbreviations in both and in Table have been defined but some need additional is used for of mineralized bone volume and is given by volume osteoid Osteoid may need to be as or as the in the lexicon between which refers to a and which refers to a for all measurements are with the indices discussed is a general term applicable to all tissue that is not and includes marrow in cancellous bone and Haversian and canals in cortical bone. For both types of tissue, can with area measurements on individual such as cells or cortical The profiles can be as an of tissue, by use of the appropriate referent. For is the area of all cell profiles referred to the area of tissue and in terms. The profiles can also be as individual by absence of a is the mean area of individual If confusion is the term be as or mean areas in cannot be to mean volumes in unless the structures are in cylindrical mean area can be used to but it is to this as described later. Osteoid do not so that some width should be for measurement of osteoid surface We the terms formation surface and resorption surface because the implications of current may be and for the same reason we the surface is with or lacunar surface and the osteoclast surface and the surface individual can also be as osteoclast or osteoclast Some cells and methods are needed for and the cells on the surface or cells. surface is with or the term that will at some future The of connective tissue the flat lining cells on quiescent surfaces should not be referred to as It is possible that some surface by flat lining cells should be as quiescent surface rather than as In all distance measurements can be obtained in two by measurement at multiple or by calculation from measurements of area and The method is more and can a and a standard deviation as well as a mean but that measurement be randomly The method is less and less to sampling The method is usually used for distance between and cell and dimensions, and the method is usually used for thickness diameter and methods are widely used for osteoid thickness and cortical The method is for the from the relationships between individual measurement at particular and at particular during the The mean determined by either method in an individual be distinguished from the mean in a of Mineralized thickness is the distance from the line to the between bone and It is used in and in different types of osteoid and different stages of in the mean should be to the between thickness and osteoid thickness is measured on an individual it has been used in the for calculation of the of and in human subjects as an of in thickness is the mean distance between on of a usually as for the is an of bone from the cortical surface, but too is known of the internal of iliac cortical bone to

CONTEXT: The cognitive and behavioral outcomes of school-aged children who were born preterm have been reported extensively. Many of these studies have methodological flaws that preclude an accurate estimate of the long-term outcomes of prematurity. OBJECTIVE: To estimate the effect of preterm birth on cognition and behavior in school-aged children. DATA SOURCES: MEDLINE search (1980 to November 2001) for English-language articles, supplemented by a manual search of personal files maintained by 2 of the authors. STUDY SELECTION: We included case-control studies reporting cognitive and/or behavioral data of children who were born preterm and who were evaluated after their fifth birthday if the attrition rate was less than 30%. From the 227 reviewed studies, cognitive data from 15 studies and behavioral data from 16 studies were selected. DATA EXTRACTION: Data on population demographics, study characteristics, and cognitive and behavioral outcomes were extracted from each study, entered in a customized database, and reviewed twice to minimize error. Differences between the mean cognitive scores of cases and controls were pooled. Homogeneity across studies was formally tested using a general variance-based method and graphically using Galbraith plots. Linear meta-analysis regression models were fitted to explore the impact of birth weight and gestational age on cognitive outcomes. Study-specific relative risks (RRs) were calculated for the incidence of attention-deficit/hyperactivity disorder (ADHD) and pooled. Quality assessment of the studies was performed based on a 10-point scale. Publication bias was examined using Begg modified funnel plots and formally tested using the Egger weighted-linear regression method. DATA SYNTHESIS: Among 1556 cases and 1720 controls, controls had significantly higher cognitive scores compared with children who were born preterm (weighted mean difference, 10.9; 95% confidence interval [CI], 9.2-12.5). The mean cognitive scores of preterm-born cases and term-born controls were directly proportional to their birth weight (R(2) = 0.51; P<.001) and gestational age (R(2) = 0.49; P<.001). Age at evaluation had no significant correlation with mean difference in cognitive scores (R(2) = 0.12; P =.20). Preterm-born children showed increases in externalizing and internalizing behaviors in 81% of studies and had more than twice the RR for developing ADHD (pooled RR, 2.64; 95% CI, 1.85-3.78). No differences were noted in cognition and behaviors based on the quality of the study. CONCLUSIONS: Children who were born preterm are at risk for reduced cognitive test scores and their immaturity at birth is directly proportional to the mean cognitive scores at school age. Preterm-born children also show an increased incidence of ADHD and other behaviors.

The adult skeleton regenerates by temporary cellular structures that comprise teams of juxtaposed osteoclasts and osteoblasts and replace periodically old bone with new.A considerable body of evidence accumulated during the last decade has shown that the rate of genesis of these two highly specialized cell types, as well as the prevalence of their apoptosis, is essential for the maintenance of bone homeostasis; and that common metabolic bone disorders such as osteoporosis result largely from a derangement in the birth or death of these cells.The purpose of this article is 3-fold: 1) to review the role and the molecular mechanism of action of regulatory molecules, such as cytokines and hormones, in osteoclast and osteoblast birth and apoptosis; 2) to review the evidence for the contribution of changes in bone cell birth or death to the pathogenesis of the most common forms of osteoporosis; and 3) to highlight the implications of bone cell birth and death for a better understanding of the mechanism of action and efficacy of present and future pharmacotherapeutic agents for osteoporosis.(Endocrine Reviews 21: 115-137, 2000) I. Introduction II.Physiological Bone Regeneration A. Remodeling by the basic multicellular unit (BMU) III.Osteoblastogenesis and Osteoclastogenesis A. Growth factors and their antagonists B. Cytokines C. Systemic hormones D. Adhesion molecules IV.Reciprocal Relationship Between Osteoblastogenesis and Adipogenesis V. Serial and Parallel Models of Osteoblast and Osteoclast Development VI. Function of the Mature Cells A. Osteoblasts B. Osteocytes C. Lining cells D. Osteoclasts VII.Death of Bone Cells by Apoptosis VIII.Regulation of Bone Cell Proliferation and Activity IX.Pathogenesis of Osteoporosis A. Sex steroid deficiency B. Senescence C. Glucocorticoid excess X.

BACKGROUND: Studies have documented the underrepresentation of women and blacks in clinical trials, and their recruitment is now federally mandated. However, little is known about the level of participation of elderly patients. We determined the rates of enrollment of patients 65 years of age or older in trials of treatment for cancer. METHODS: We analyzed data on 16,396 patients consecutively enrolled in 164 Southwest Oncology Group treatment trials between 1993 and 1996 according to sex, race (black or white), and age under 65 years or 65 or older. These rates were compared with the corresponding rates in the general population of patients with cancer, derived from the 1990 U.S. Census and from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program for the period from 1992 through 1994. Fifteen types of cancer were included in the analysis. RESULTS: The overall proportions of women and blacks enrolled in Southwest Oncology Group trials were similar to or the same as the estimated proportions in the U.S. population of patients with cancer (women, 41 percent and 43 percent; blacks, 10 percent and 10 percent, respectively). In contrast, patients 65 years of age or older were underrepresented overall (25 percent vs. 63 percent, P<0.001) and in trials involving all 15 types of cancer except lymphoma. The underrepresentation was particularly notable in trials of treatment for breast cancer (9 percent vs. 49 percent, P<0.001). The findings were similar when data on patients who were 70 years of age or older were analyzed, when 15 trials that excluded older patients were eliminated from the analysis, and when community-based enrollment was analyzed separately from enrollment at academic centers. CONCLUSIONS: There is substantial underrepresentation of patients 65 years of age or older in studies of treatment for cancer. The reasons should be clarified, and policies adopted to correct this underrepresentation.

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

PROBLEM/CONDITION: Autism spectrum disorder (ASD). PERIOD COVERED: 2012. DESCRIPTION OF SYSTEM: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that provides estimates of the prevalence and characteristics of ASD among children aged 8 years whose parents or guardians reside in 11 ADDM Network sites in the United States (Arkansas, Arizona, Colorado, Georgia, Maryland, Missouri, New Jersey, North Carolina, South Carolina, Utah, and Wisconsin). Surveillance to determine ASD case status is conducted in two phases. The first phase consists of screening and abstracting comprehensive evaluations performed by professional service providers in the community. Data sources identified for record review are categorized as either 1) education source type, including developmental evaluations to determine eligibility for special education services or 2) health care source type, including diagnostic and developmental evaluations. The second phase involves the review of all abstracted evaluations by trained clinicians to determine ASD surveillance case status. A child meets the surveillance case definition for ASD if one or more comprehensive evaluations of that child completed by a qualified professional describes behaviors that are consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnostic criteria for any of the following conditions: autistic disorder, pervasive developmental disorder-not otherwise specified (including atypical autism), or Asperger disorder. This report provides ASD prevalence estimates for children aged 8 years living in catchment areas of the ADDM Network sites in 2012, overall and stratified by sex, race/ethnicity, and the type of source records (education and health records versus health records only). In addition, this report describes the proportion of children with ASD with a score consistent with intellectual disability on a standardized intellectual ability test, the age at which the earliest known comprehensive evaluation was performed, the proportion of children with a previous ASD diagnosis, the specific type of ASD diagnosis, and any special education eligibility classification. RESULTS: For 2012, the combined estimated prevalence of ASD among the 11 ADDM Network sites was 14.5 per 1,000 (one in 69) children aged 8 years. Estimated prevalence was significantly higher among boys aged 8 years (23.4 per 1,000) than among girls aged 8 years (5.2 per 1,000). Estimated ASD prevalence was significantly higher among non-Hispanic white children aged 8 years (15.3 per 1,000) compared with non-Hispanic black children (13.1 per 1,000), and Hispanic (10.2 per 1,000) children aged 8 years. Estimated prevalence varied widely among the 11 ADDM Network sites, ranging from 8.2 per 1,000 children aged 8 years (in the area of the Maryland site where only health care records were reviewed) to 24.6 per 1,000 children aged 8 years (in New Jersey, where both education and health care records were reviewed). Estimated prevalence was higher in surveillance sites where education records and health records were reviewed compared with sites where health records only were reviewed (17.1 per 1,000 and 10.4 per 1,000 children aged 8 years, respectively; p<0.05). Among children identified with ASD by the ADDM Network, 82% had a previous ASD diagnosis or educational classification; this did not vary by sex or between non-Hispanic white and non-Hispanic black children. A lower percentage of Hispanic children (78%) had a previous ASD diagnosis or classification compared with non-Hispanic white children (82%) and with non-Hispanic black children (84%). The median age at earliest known comprehensive evaluation was 40 months, and 43% of children had received an earliest known comprehensive evaluation by age 36 months. The percentage of children with an earliest known comprehensive evaluation by age 36 months was similar for boys and girls, but was higher for non-Hispanic white children (45%) compared with non-Hispanic black children (40%) and Hispanic children (39%). INTERPRETATION: Overall estimated ASD prevalence was 14.5 per 1,000 children aged 8 years in the ADDM Network sites in 2012. The higher estimated prevalence among sites that reviewed both education and health records suggests the role of special education systems in providing comprehensive evaluations and services to children with developmental disabilities. Disparities by race/ethnicity in estimated ASD prevalence, particularly for Hispanic children, as well as disparities in the age of earliest comprehensive evaluation and presence of a previous ASD diagnosis or classification, suggest that access to treatment and services might be lacking or delayed for some children. PUBLIC HEALTH ACTION: The ADDM Network will continue to monitor the prevalence and characteristics of ASD among children aged 8 years living in selected sites across the United States. Recommendations from the ADDM Network include enhancing strategies to 1) lower the age of first evaluation of ASD by community providers in accordance with the Healthy People 2020 goal that children with ASD are evaluated by age 36 months and begin receiving community-based support and services by age 48 months; 2) reduce disparities by race/ethnicity in identified ASD prevalence, the age of first comprehensive evaluation, and presence of a previous ASD diagnosis or classification; and 3) assess the effect on ASD prevalence of the revised ASD diagnostic criteria published in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.