Northwestern Memorial Hospital

The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists; focal seizures should be described according to their manifestations (e.g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural-metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural-metabolic causes, and epilepsies of unknown cause. Further organization within these divisions can be accomplished in a flexible manner depending on purpose. Natural classes (e.g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e.g., epileptic encephalopathies, self-limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms.

OBJECTIVE: The goal of this study was to better estimate the prevalence and severity of childhood food allergy in the United States. METHODS: A randomized, cross-sectional survey was administered electronically to a representative sample of US households with children from June 2009 to February 2010. Eligible participants included adults (aged 18 years or older) able to complete the survey in Spanish or English who resided in a household with at least 1 child younger than 18 years. Data were adjusted using both base and poststratification weights to account for potential biases from sampling design and nonresponse. Data were analyzed as weighted proportions to estimate prevalence and severity of food allergy. Multiple logistic regression models were constructed to identify characteristics significantly associated with outcomes. RESULTS: Data were collected for 40 104 children; incomplete responses for 1624 children were excluded, which yielded a final sample of 38 480. Food allergy prevalence was 8.0% (95% confidence interval [CI]: 7.6-8.3). Among children with food allergy, 38.7% had a history of severe reactions, and 30.4% had multiple food allergies. Prevalence according to allergen among food-allergic children was highest for peanut (25.2% [95% CI: 23.3-27.1]), followed by milk (21.1% [95% CI: 19.4-22.8]) and shellfish (17.2% [95% CI: 15.6-18.9]). Odds of food allergy were significantly associated with race, age, income, and geographic region. Disparities in food allergy diagnosis according to race and income were observed. CONCLUSIONS: Findings suggest that the prevalence and severity of childhood food allergy is greater than previously reported. Data suggest that disparities exist in the clinical diagnosis of disease.

Children with medical complexity (CMC) have medical fragility and intensive care needs that are not easily met by existing health care models. CMC may have a congenital or acquired multisystem disease, a severe neurologic condition with marked functional impairment, and/or technology dependence for activities of daily living. Although these children are at risk of poor health and family outcomes, there are few well-characterized clinical initiatives and research efforts devoted to improving their care. In this article, we present a definitional framework of CMC that consists of substantial family-identified service needs, characteristic chronic and severe conditions, functional limitations, and high health care use. We explore the diversity of existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. Finally, we suggest a research agenda that uses a uniform definition to accurately describe the population and to evaluate outcomes from the perspectives of the child, the family, and the broader health care system.

Table: of ContentsA. EXECUTIVE SUMMARY Updated US consensus guidelines for management of cervical screening abnormalities are needed to accommodate the 3 available cervical screening strategies: primary human papillomavirus (HPV) screening, cotesting with HPV testing and cervical cytology, and cervical cytology alone. New data indicate that a patient's risk of developing cervical precancer or cancer can be estimated using current screening test results and previous screening test and biopsy results, while considering personal factors such as age and immunosuppression. Routine screening applies only to asymptomatic individuals who do not require surveillance for prior abnormal screening results. The 2012 consensus guidelines were the first to be based on the principle of equal management for equal risk, specifically, the risk of a patient developing cervical cancer, estimated by the surrogate end point of the 5-year risk of cervical intraepithelial neoplasia (CIN) grade 3 (CIN 3) or more severe diagnoses (CIN 3+), regardless of which test combinations yielded this risk level. Introduction of risk-based guidelines in 2012 was a conceptual breakthrough, but the recommendations retained a continued reliance on complicated algorithms and insufficiently incorporated screening history. With a more nuanced understanding of how previous results affect risk, and more variables to consider, the 2019 guidelines further align management recommendations with current understanding of HPV natural history and cervical carcinogenesis. More frequent surveillance, colposcopy, and treatment are recommended for patients at progressively higher risk, whereas those at lower risk can defer colposcopy, undergo follow-up at longer surveillance intervals, and, when at sufficiently low risk, return to routine screening. Clearly defined risk thresholds to guide management are designed to continue functioning appropriately when population-level prevalence of CIN 3+ decreases because of HPV vaccination and also as new screening and triage tests are introduced. The revised guidelines provide a framework for incorporating new data and technologies as ongoing incremental recommendation revisions, minimizing the time needed to implement changes that are beneficial to patient care. B. INTRODUCTION This is the fourth American Society of Colposcopy and Cervical Pathology (ASCCP)-sponsored consensus guidelines for management of cervical cancer screening abnormalities, after the original consensus conferences in 20011 and subsequent updates in 20062 and 2012.3 An interim guidance publication providing management recommendations for primary HPV screening was released in 2015.4This document updates and replaces all previous guidance. The key difference between 2019 guidelines and previous versions is the change from primarily test results–based algorithms (e.g., "Colposcopy is recommended for patients with HPV-positive atypical squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial lesion [LSIL]," etc.) to primarily "risk-based" guidelines (e.g., "Colposcopy is recommended for any combination of history and current test results yielding a 4.0% or greater probability of finding CIN 3+," etc.). See Box 1 for essential changes. Tables of risk estimates for possible combinations of current screening test results and screening history (including unknown history) have been generated from a prospective longitudinal cohort of more than 1.5 million patients followed for more than a decade at Kaiser Permanente Northern California (KPNC). All KPNC estimates of risk underlying guideline decisions are detailed in the accompanying article by Egemen et al.5 The applicability of these risk estimates to other United States regions and populations has been confirmed in other data sets from screening programs and clinical trials.6 Many patients, especially those with minor abnormalities, can be managed by identifying their risk level using Tables 1A to 5B in Egemen et al5 and linking it to a recommended clinical action (return to routine screening, surveillance with repeat testing at 1- or 3-year intervals, colposcopy, or treatment). To facilitate use of these tables, the same information will be accessible via smartphone app (for purchase) and web (no cost) through http://www.asccp.org. Decision aids may facilitate use of the tables.7 Common abnormalities are managed using risk estimates outlined in Section E, and rare abnormalities are managed via the result-specific consensus recommendations outlined in Sections G-K.TABLE 1: Participating OrganizationsBox 1. Essential Changes From Prior Management Guidelines 1) Recommendations are based on risk, not results. Recommendations of colposcopy, treatment, or surveillance will be based on a patient's risk of CIN 3+ determined by a combination of current results and past history (including unknown history). The same current test results may yield different management recommendations depending on the history of recent past test results. 2) Colposcopy can be deferred for certain patients. Repeat HPV testing or cotesting at 1 year is recommended for patients with minor screening abnormalities indicating HPV infection with low risk of underlying CIN 3+ (e.g., HPV-positive, low-grade cytologic abnormalities after a documented negative screening HPV test or cotest). 3) Guidance for expedited treatment is expanded (i.e., treatment without colposcopic biopsy). Expedited treatment was an option for patients with HSIL cytology in the 2012 guidelines; this guidance is now better defined. For non-pregnant patients 25 years or older, expedited treatment, defined as treatment without preceding colposcopic biopsy demonstrating CIN 2+, is preferred when the immediate risk of CIN 3+ is ≥60%, and is acceptable for those with risks between 25% and 60%. Expedited treatment is preferred for nonpregnant patients 25 years or older with high-grade squamous intraepithelial lesion (HSIL) cytology and concurrent positive testing for HPV genotype 16 (HPV 16) (i.e., HPV 16–positive HSIL cytology) and never or rarely screened patients with HPV-positive HSIL cytology regardless of HPV genotype. Shared decision-making should be used when considering expedited treatment, especially for patients with concerns about the potential impact of treatment on pregnancy outcomes. 4) Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN 2 or CIN 3) in the United States. Excision is recommended for adenocarcinoma in situ (AIS). 5) Observation is preferred to treatment for CIN 1. 6) Histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World Health Organization (WHO) recommendations for reporting histologic HSIL should include CIN 2 or CIN 3 qualifiers, i.e., HSIL(CIN 2) and HSIL (CIN 3). 7) All positive primary HPV screening tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory specimen (e.g., reflex cytology). Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy practice. For example, those HPV-16 positive HSIL cytology qualify for expedited treatment. HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (e.g., colposcopy with biopsy) is necessary even when cytology results are negative. If HPV 16 or 18 testing is positive, and additional laboratory testing of the same sample is not feasible, the patient should proceed directly to colposcopy. 8) Continued surveillance with HPV testing or cotesting at 3-year intervals for at least 25 years is recommended after treatment and initial post-treatment management of histologic HSIL, CIN 2, CIN 3, or AIS. Continued surveillance at 3-year intervals beyond 25 years is acceptable for as long as the patient's life expectancy and ability to be screened are not significantly compromised by serious health issues. The 2012 guidelines recommended return to 5-year screening intervals and did not specify when screening should cease. New evidence indicates that risk remains elevated for at least 25 years, with no evidence that treated patients ever return to risk levels compatible with 5-year intervals. 9) Surveillance with cytology alone is acceptable only if testing with HPV or cotesting is not feasible. Cytology is less sensitive than HPV testing for detection of precancer and is therefore recommended more often. Cytology is recommended at 6-month intervals when HPV testing or cotesting is recommended annually. Cytology is recommended annually when 3-year intervals are recommended for HPV or cotesting. 10) Human papilloma virus assays that are Food and Drug Administration (FDA)-approved for screening should be used for management according to their regulatory approval in the United States. (Note: all HPV testing in this document refers to testing for high-risk HPV types only). For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should only be used as a cotest with cytology, unless sufficient, rigorous data are available to support use of these particular tests in management. The minimum amount of data required to generate a recommendation will include the patient's age and current test results, as we recognize that previous screening history is often not known. Increased precision of management guidance will be possible if information is available on test results within the past 5 years and previous precancer treatment within the past 25 years.3 Current results and past history are designed to generate the patient's risk estimate from data tables.5 Risk estimates are available for the following clinical situations: abnormal screening test results with unknown history, abnormal screening test results with medical record documentation of a preceding negative HPV test or cotest, surveillance of previous abnormal screening test results that did not require immediate colposcopic referral (e.g., follow-up after an HPV-positive cytology negative result), colposcopy/biopsy results, and follow-up surveillance tests after colposcopy or after treatment for, or resolution of, high-grade abnormalities (e.g., CIN 2+). The recognition that persistent HPV infection is necessary for developing precancer and cancer (defined as CIN 3+, which includes diagnoses of CIN 3, AIS, and cancer) underlies the 2019 guideline update. Prospective longitudinal data indicate that when a new abnormal screening test result follows a negative HPV test or cotest within the past 5 years, the estimated risk of CIN 3+ is reduced by approximately 50%.8 A negative cytology result within 3 years of a new abnormal screening test, however, does not confer a similar reduction in risk.9 The 2019 guidelines also recognize that a colposcopic examination performed according to accepted standards (e.g., using the KPNC colposcopy protocol or the ASCCP Colposcopy Standards10) confirming low-grade or normal histology reduces a patient's estimated risk of having precancer/cancer in the next 2 years.11 This allows patients with an HPV-positive ASC-US or LSIL result at their 1-year follow-up visit after a colposcopy confirming normal- or low-grade histology to return for repeat HPV or cotesting in 1 more year, rather than immediately return to colposcopy. Thus, incorporating a patient's history of previous HPV tests and colposcopy/biopsy results will permit detection and treatment of CIN 3+ while avoiding unnecessary interventions for patients with new HPV infections who are at lower risk.12 C. GUIDING PRINCIPLES Guidelines are based on several guiding principles. The first 4 guiding principles are new for 2019, whereas the others are from the 2012 guidelines. As the 2012 guidelines are familiar to providers, we changed management recommendations only when new evidence favored an altered management strategy. Note that management guidelines apply only to patients with current or previous abnormal screening test results; screening guidelines for individuals in the general population, that are not being followed for a screening abnormality, are addressed elsewhere.13,14 New 2019 Principles 1. HPV–based testing is the basis for risk estimation. The term HPV-based testing is used throughout this document and refers to use of either primary HPV testing alone or HPV testing in conjunction with cervical cytology (cotesting). Characteristics of HPV infections, including HPV type and the duration of infection, determine a patient's risk of CIN 3+.15–18 Although cytology has high specificity (apart from ASC-US) and can be helpful when estimating immediate risk, its lower sensitivity and lower negative predictive value compared with HPV testing reduces its utility for long-term risk prediction.9 The results of HPV tests alone or in conjunction with cytology are used to guide recommendations that allow lengthening of follow-up intervals and deferral of colposcopy for low-risk results. Of note, risk estimates underlying the 2019 management guidelines are based on HPV DNA testing. 2.Personalized risk-based management is possible with knowledge of current results and past history. A patient's risk of having or developing CIN 3+ is estimated based on current and previous results, as well as history of previous precancer treatment. Management recommendations use thresholds of risk.19 Recommendations of routine screening, 1-year or 3-year surveillance, colposcopy, or treatment correspond to a risk stratum, a range of risk for CIN 3+. The lower threshold of each risk stratum, called Clinical Action Threshold, defines the level at which the management recommendation changes. The Clinical Action Thresholds for each risk stratum were determined through the consensus process. Risks were estimated for all combination of current results and past history (including unknown history) for which adequate data were available at KPNC. Management can be determined via look-up tables,5 and use of the tables can be facilitated using decision aids. 3.Guidelines must allow updates to incorporate new test methods as they are validated, and to adjust for decreasing CIN3+ risks as more patients who received HPV vaccination reach screening age. The field of cervical cancer prevention is rapidly evolving, with new technologies being continually validated. Data on the validation of new technologies are being published frequently, and risk reduction from HPV vaccination is increasing as vaccine coverage increases and vaccinated individuals age into screening cohorts. Up to now, guideline revisions have required full consensus conferences, which are time-consuming, expensive, and not compatible with the rapid evolution of the field. The 2019 guidelines build a framework that allows incorporation of new technologies and modified strategies without requiring full consensus conferences, so that revisions may rapidly incorporate new findings and be quickly disseminated to optimize patient care. Clinical Action Thresholds for management created through the 2019 consensus process will remain in place, but as new tests become available and more long-term data accrue, the test combinations used to reach these thresholds will change. For example, at the 2019 consensus conference, HPV vaccination levels in the United States population currently 25 years or older were deemed too low to warrant incorporating HPV vaccination into the 2019 management recommendations. However, this is expected to change in the near future as more vaccinated patients, who have lower CIN 3+ risk, reach the age of 25 years and additional data accrue demonstrating the impact of vaccination on the CIN 3+ risk associated with abnormal test result combinations. The framework outlined here will allow guideline modification as robust data become available and are publicized. Because Clinical Action Thresholds remain constant, new data can be added while the Clinical Action Thresholds remain unchanged. This design is intentional to reduce clinician confusion associated with frequently changing guidelines. 4.Colposcopy practice must follow guidance detailed in the ASCCP Colposcopy Standards.10 Colposcopy with targeted biopsy remains the primary method of detecting precancers requiring treatment. Because patients are managed less aggressively after a colposcopic examination where CIN grade 2 or higher (CIN 2+) is not found, maximizing detection of CIN 2+ at each colposcopy visit is paramount. Evidence-based practice recommends that biopsies be taken of all discrete acetowhite areas, usually 2 to 4 biopsies at each colposcopic examination. For those at lowest risk, defined as less than HSIL cytology, no evidence of HPV 16/18 infection, and a completely normal colposcopic impression (i.e., no acetowhitening, metaplasia, or other visible abnormality, and a fully visualized squamocolumnar junction), untargeted (random) biopsies are not recommended and patients with a completely normal colposcopic impression can be observed without biopsy. To ensure that CIN 2+ is not missed, the ASCCP Colposcopy Standards emphasize the need for biopsies even when the colposcopic impression is normal but any degree of acetowhitening, metaplasia, or other abnormality is present. 2012 Principles Carried Forward 5.The primary goal of screening and management is cancer prevention through detection and treatment of cervical precancer. Numerous population-level studies indicate that incidence and mortality from cervical cancer decrease as detection and treatment of high-grade histologic cervical abnormalities (generally defined as CIN 2+) increases.20,21 Timely detection and treatment of the highest grade of precancers (CIN 3/AIS) have been the benchmark used for previous guidelines3 and remain the primary goal of the 2019 management guideline; a secondary goal (because of the relative rarity of this finding in the United States) is early diagnosis of cervical cancer to reduce related morbidity and mortality. A patient's risk of having or developing CIN 3+ is estimated based on current and previous results, as well as history of previous precancer treatment. Management recommendations are guided by risk thresholds.19 Recommendations of routine screening, 1- or 3-year surveillance, colposcopy, or treatment each correspond to a risk stratum. These risk strata (ranges of risk for CIN 3+) are defined by Clinical Action Thresholds that were determined through the consensus process (Section E). 6.Guidelines apply to all individuals with a cervix. Guidelines apply to women and transgender men with a cervix, including individuals who have undergone supracervical hysterectomy. Risk estimates were validated in individuals of diverse racial, ethnic, and socioeconomic backgrounds and shown to be comparable.6 Though not the primary focus of the 2019 guidelines, management recommendations are also provided for patients who have undergone hysterectomy with removal of the cervix and who have a previous diagnosis of histologic HSIL, CIN 2, CIN 2/3, CIN 3, and/or AIS, irrespective of whether the hysterectomy was performed for precancer treatment or another indication. 7.Equal management for equal risk. History and current test results are used to calculate a patient's current and future risk of CIN 3+. Similar risks are managed similarly, regardless of the combination of results/history used to estimate the risk. 8.Balancing benefits and harms. Providing the best care means balancing cancer prevention with overtesting and overtreatment. Preventing all cervical cancers is unfortunately not an achievable goal. Interventions to prevent cervical cancer can cause harm. The 2019 guidelines are designed to maximize cervical cancer prevention and minimize harms from overtesting and overtreating by managing patients according to their current and future risks of CIN 3+. High-risk patients require closer follow-up to maximize detection of CIN 3+, whereas low-risk patients require fewer tests and procedures. 9.Guidelines apply to asymptomatic patients that require management of abnormal cervical screening test results. Patients with symptoms such as abnormal uterine or vaginal bleeding or a visibly abnormal-appearing cervix require appropriate diagnostic testing as this may be a sign of cancer.22 This evaluation may include cervical cytology, colposcopy, diagnostic imaging, and cervical, endocervical, or endometrial biopsy. Guidelines cannot cover all clinical situations and clinical judgment is advised, especially in those circumstances which are not covered by the 2019 guidelines. 10.Guidelines are intended for use in the United States. Appropriate management may differ in countries with limited follow-up capabilities, less availability of colposcopy, limited pathology infrastructure, or different views of the trade-offs between cancer risk, cost, and overtesting/overtreatment. D. METHODS D.1 Process and Timeline The ASCCP and National Cancer Institute (NCI) established a Memorandum of Understanding in January 2017 to undertake the work of this guideline update. As with the previous 2001, 2006, and 2012 guidelines,1–3 NCI produced risk data and other scientific support for the consensus guideline process. The ASCCP sponsored the consensus effort to develop and ratify the guidelines. Stakeholder organizations representing best practice in the United States were identified and invited to participate. These included medical professional societies, patient advocacy groups, and federal agencies integral to cervical cancer screening and management of abnormal results (see Table 1). Participation of the stakeholder organizations included identifying organization representatives and, for nongovernment participants, sponsoring their travel to consensus conferences. Representatives from 19 organizations attended the initial meeting in February 2018. At that time, 7 working groups were convened. In previous consensus conferences, working groups considered test (e.g., and In the 7 working groups for the 2019 guidelines were with the goal of consensus Clinical Action The treatment which risk levels of CIN 3+ warrant expedited treatment without as well as issues. The colposcopy considered the threshold for colposcopy The surveillance created a of at intervals than currently recommended for routine screening with either HPV primary testing or cotesting and also when patients return to routine screening. Patients surveillance include those with abnormal screening results not requiring colposcopy (e.g., HPV-positive for or after colposcopy with low-grade results, or after treatment for high-grade The risk modification factors that change a patient's estimated risk or on pregnancy and immunosuppression. The high value care performed decision related to management strategies and will continue to value as the 2019 guidelines are The new technologies laboratory and technologies related to management. The created and for to and the about the guidelines and the process. groups were of 2 to including representatives of stakeholder and representatives of patient advocacy groups from through 2019 to data and develop guidelines for management. The consensus process was by a by the ASCCP and was by a of 1 NCI and 2 ASCCP representatives Because the guidelines a the guidelines process included a and process of stakeholder These included patient and a consensus meeting to guidelines, and a the consensus meeting in of CIN 3+ as Clinical for Risk For the management guidelines, we CIN 3+ as the best surrogate for cancer risk. The of CIN 3+ as used in these guidelines includes CIN 3, AIS, and the rare of cervical cancer that are in screening These management guidelines CIN 3+ risk at the time point for the clinical action being Action Thresholds for colposcopy and treatment immediate risks of CIN 3+, whereas surveillance recommendations use 5-year CIN3+ was as an of cancer because cancer is in the United and risk is by treatment. that are in robust screening programs may cancers at first screening, rare of or not by screening, or negative CIN 3+ was of CIN 2+ because it is a more the HPV type in CIN 3+ more that of cervical cancers than the range of types in CIN and CIN 2 has in the of The of CIN 3+ does have as even CIN risks of to cancer including AIS, with HPV 16 and 18 infections, and those in older patients have higher cancer risks than and those in for cervical are in use in the United States. The and the a for reporting of squamous similar to the used for reporting cervical However, the CIN is and data used to generate this of guidelines on CIN Although no is possible without use of the histologic HSIL is similar but not to CIN Data to Risks Prior guidelines on a prospective data including results of cytology, HPV colposcopy, and follow-up from which cotesting as practice in The KPNC data continue to be the data in the United States for risk of combinations of HPV DNA testing and For the 2019 guidelines, several additional were to ensure that results are to patients of diverse racial, ethnic, and socioeconomic Risk estimates were compared using screening and follow-up data from clinical a HPV and the for and National and Cervical Cancer a that includes and The populations in of abnormal screening results and the prevalence of CIN 3+. the that the risks of CIN 3+ for the combination of current results and screening history were similar in that they within the same risk for management. et the of CIN 3+ risks associated with screening test result combinations the different populations of screened patients from these data In different populations within the United States have higher or lower of CIN 3+ to factors including to screening and HPV infection patients with similar test results and screening history combinations have similar CIN 3+ risk, regardless of their or socioeconomic of Risks of how risks of CIN 3+ were for the combinations of test results, including longitudinal of tests time, are in the accompanying In for each combination of past and current test results, the risk of CIN 3+ was estimated using which of of CIN 3+ at the time of the current testing using a and CIN 3+ at subsequent testing using a These are designed to and in this means that are only available for patients to CIN3+ that in the of negative screening or abnormal screening tests that were not for colposcopy will not be in this means that the CIN 3+ is at colposcopy but the time of of CIN 3+ cannot be determined as it is asymptomatic and between testing These are designed to provide risk estimates without the data into a (e.g., of to Clinical For each combination of current test results and screening

BACKGROUND: Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. METHODS: We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). RESULTS: The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. CONCLUSIONS: In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. no immunosuppressants IV D no nasal saline irrigation Ib, no data in single use D yes for symptomatic relief topical antibiotics no data D no anti-IL-5 no data D unclear phytotherapy no data D no decongestant topical / oral no data in single use D no mucolytics no data D no oral antihistamine in allergic patients no data D no antimycotics -topical Ia (-) ** A(-) no antimycotics -systemic Ib (-)# A(-) $ no anti leukotrienes Ib (-) A(-) no anti-IgE Ib (-) A(-) no * Some of these studies also included patients with CRS with nasal polyps. % short term antibiotics shows one positive and one negative study. Therefore recommendation C. oral antibiotic short term <4 weeks Ib(-) # A(-)* no intravenous antibiotics III(-) ## C(-) ** no # Ib (-): Ib study with a negative outcome.

Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population-based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies.

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

With the increasing use of cocaine in the United States, there has been growing concern regarding its effects on the fetuses and neonates of pregnant cocaine abusers. Twenty-three cocaine-using women enrolled in a comprehensive perinatal-addiction program were divided into two groups: those using cocaine only and those using cocaine plus narcotics. These two groups were compared with a group of women who had used narcotics in the past and were maintained on methadone during pregnancy, and with a group of drug-free women. All four groups were similar in maternal age, socioeconomic status, number of pregnancies, and cigarette, marijuana, and alcohol use. Their medical histories indicated that the cocaine-using women had a significantly higher rate of spontaneous abortion than the women in the other two groups. In the pregnancies under study, four cocaine-using women had onset of labor with abruptio placentae immediately after intravenous self-injection of cocaine. Neonatal gestational age, birth weight, length, and head circumference were not affected by cocaine use. However, the Brazelton Neonatal Behavioral Assessment Scale revealed that infants exposed to cocaine had significant depression of interactive behavior and a poor organizational response to environmental stimuli (state organization). These preliminary observations suggest that cocaine influences the outcome of pregnancy as well as the neurologic behavior of the newborn, but a full assessment will require a larger number of pregnancies and longer follow-up.

Learning by doing represents an important mechanism through which organizations prosper. Some firms, however, learn from their experience at a dramatic rate, while other firms exhibit very little learning at all. Three factors have been identified that affect the rate at which firms learn: (a) the proficiency of individual workers, (b) the ability of firm members to leverage knowledge accumulated by others, and (c) the capacity for coordinated activity inside the organization. Each factor varies with a particular kind of experience. An increase in cumulative individual experience increases individual proficiency. An increase in cumulative organizational experience provides individuals with the opportunity to benefit from knowledge accumulated by others. An increase in cumulative experience working together promotes more effective coordination and teamwork. To gain insight into factors responsible for the learning curve, we examine the contribution of each kind of experience to performance, while controlling for the impact of the other two. The study context is a teaching hospital. The task is a total joint replacement procedure, and the performance metric is procedure completion time. We find that each kind of experience makes a distinct contribution to team performance. We discuss the implications of our findings for the learning-by-doing framework in general, and learning in the team context in particular.

In 2003, the American Cancer Society updated its guidelines for early detection of breast cancer based on recommendations from a formal review of evidence and a recent workshop. The new screening recommendations address screening mammography, physical examination, screening older women and women with comorbid conditions, screening women at high risk, and new screening technologies.

While medications can improve patients' health, the process of prescribing them is complex and error prone, and medication errors cause many preventable injuries. Computer provider order entry (CPOE) with clinical decision support (CDS), can improve patient safety and lower medication-related costs. To realize the medication-related benefits of CDS within CPOE, one must overcome significant challenges. Healthcare organizations implementing CPOE must understand what classes of CDS their CPOE systems can support, assure that clinical knowledge underlying their CDS systems is reasonable, and appropriately represent electronic patient data. These issues often influence to what extent an institution will succeed with its CPOE implementation and achieve its desired goals. Medication-related decision support is probably best introduced into healthcare organizations in two stages, basic and advanced. Basic decision support includes drug-allergy checking, basic dosing guidance, formulary decision support, duplicate therapy checking, and drug-drug interaction checking. Advanced decision support includes dosing support for renal insufficiency and geriatric patients, guidance for medication-related laboratory testing, drug-pregnancy checking, and drug-disease contraindication checking. In this paper, the authors outline some of the challenges associated with both basic and advanced decision support and discuss how those challenges might be addressed. The authors conclude with summary recommendations for delivering effective medication-related clinical decision support addressed to healthcare organizations, application and knowledge base vendors, policy makers, and researchers.

The authors present a four-step model of debriefing as formative assessment that blends evidence and theory from education research, the social and cognitive sciences, experience drawn from conducting over 3,000 debriefings, and teaching debriefing to approximately 1,000 clinicians worldwide. The steps are to: 1) note salient performance gaps related to predetermined objectives, 2) provide feedback describing the gap, 3) investigate the basis for the gap by exploring the frames and emotions contributing to the current performance level, and 4) help close the performance gap through discussion or targeted instruction about principles and skills relevant to performance. The authors propose that the model, designed for postsimulation debriefings, can also be applied to bedside teaching in the emergency department (ED) and other clinical settings.

BACKGROUND: Mechanical circulatory support with a left ventricular assist device (LVAD) is an established treatment for patients with advanced heart failure. We compared a newer LVAD design (a small intrapericardial centrifugal-flow device) against existing technology (a commercially available axial-flow device) in patients with advanced heart failure who were ineligible for heart transplantation. METHODS: We conducted a multicenter randomized trial involving 446 patients who were assigned, in a 2:1 ratio, to the study (centrifugal-flow) device or the control (axial-flow) device. Adults who met contemporary criteria for LVAD implantation for permanent use were eligible to participate in the trial. The primary end point was survival at 2 years free from disabling stroke or device removal for malfunction or failure. The trial was powered to show noninferiority with a margin of 15 percentage points. RESULTS: The intention-to treat-population included 297 participants assigned to the study device and 148 participants assigned to the control device. The primary end point was achieved in 164 patients in the study group and 85 patients in the control group. The analysis of the primary end point showed noninferiority of the study device relative to the control device (estimated success rates, 55.4% and 59.1%, respectively, calculated by the Weibull model; absolute difference, 3.7 percentage points; 95% upper confidence limit, 12.56 percentage points; P=0.01 for noninferiority). More patients in the control group than in the study group had device malfunction or device failure requiring replacement (16.2% vs. 8.8%), and more patients in the study group had strokes (29.7% vs. 12.1%). Quality of life and functional capacity improved to a similar degree in the two groups. CONCLUSIONS: In this trial involving patients with advanced heart failure who were ineligible for heart transplantation, a small, intrapericardial, centrifugal-flow LVAD was found to be noninferior to an axial-flow LVAD with respect to survival free from disabling stroke or device removal for malfunction or failure. (Funded by HeartWare; ENDURANCE ClinicalTrials.gov number, NCT01166347 .).

OBJECTIVE: This study was designed to assess physicians' attitudes toward obese patients and the causes and treatment of obesity. RESEARCH METHODS AND PROCEDURES: A questionnaire assessed attitudes in 2 geographically representative national random samples of 5000 primary care physicians. In one sample (N = 2500), obesity was defined as a BMI of 30 to 40 kg/m(2), and in the other (N = 2500), obesity was defined as a BMI > 40. RESULTS: Six hundred twenty physicians responded. They rated physical inactivity as significantly more important than any other cause of obesity (p < 0.0009). Two other behavioral factors-overeating and a high-fat diet-received the next highest mean ratings. More than 50% of physicians viewed obese patients as awkward, unattractive, ugly, and noncompliant. The treatment of obesity was rated as significantly less effective (p < 0.001) than therapies for 9 of 10 chronic conditions. Most respondents (75%), however, agreed with the consensus recommendations that a 10% reduction in weight is sufficient to improve obesity-related health complications and viewed a 14% weight loss (i.e., 78 +/- 5 kg from an initial weight of 91 kg) as an acceptable treatment outcome. More than one-half (54%) would spend more time working on weight management issues if their time was reimbursed appropriately. DISCUSSION: Primary care physicians view obesity as largely a behavioral problem and share our broader society's negative stereotypes about the personal attributes of obese persons. Practitioners are realistic about treatment outcomes but view obesity treatment as less effective than treatment of most other chronic conditions.

The identification of ultraconserved noncoding sequences in vertebrates has been associated with developmental regulators and DNA-binding proteins. One of the first of these was identified in the intergenic region between the Dlx-5 and Dlx-6 genes, members of the Dlx/dll homeodomain-containing protein family. In previous experiments, we showed that Sonic hedgehog treatment of forebrain neural explants results in the activation of Dlx-2 and the novel noncoding RNA (ncRNA), Evf-1. In this report, we show that the Dlx-5/6 ultraconserved region is transcribed to generate an alternatively spliced form of Evf-1, the ncRNA Evf-2. Evf-2 specifically cooperates with Dlx-2 to increase the transcriptional activity of the Dlx-5/6 enhancer in a target and homeodomain-specific manner. A stable complex containing the Evf-2 ncRNA and the Dlx-2 protein forms in vivo, suggesting that the Evf-2 ncRNA activates transcriptional activity by directly influencing Dlx-2 activity. These experiments identify a novel mechanism whereby transcription is controlled by the cooperative actions of an ncRNA and a homeodomain protein. The possibility that a subset of vertebrate ultraconserved regions may function at both the DNA and RNA level to control key developmental regulators may explain why ultraconserved sequences exhibit 90% or more conservation even after 450 million years of vertebrate evolution.

BACKGROUND: Open spina bifida is the most complex congenital abnormality compatible with long-term survival. This report outlines the 20- to 25-year outcome for our original cohort of patients with a myelomeningocele treated in a nonselective, prospective manner. METHODS: Of the initial 118 children, 71 patients were available for our most recent review. Nineteen patients have been lost to follow-up and 28 patients have died. Data were collected on: motor level, shunt status, education/employment, seizure history, mobility, bladder/bowel continence, tethered cord, scoliosis, latex allergy, posterior cervical decompression, tracheostomy and/or gastrostomy tube. RESULTS: Mortality (24%) continues to climb into young adulthood. Eighty-six percent of the cohort have cerebrospinal fluid diversion, with 95% having undergone at least one shunt revision. Thirty-two percent have undergone a tethered cord release, with 97% having an improvement or stabilization in their preoperative symptoms. Forty-nine percent have scoliosis, with 43% eventually requiring a spinal fusion. Sixteen patients (23%) have had at least one seizure. Eighty-five percent are attending or have graduated from high school and/or college. More than 80% of young adults have social bladder continence. Approximately 1/3 of patients are allergic to latex, with 6 patients having experienced a life-threatening reaction. CONCLUSION: At least 75% of children born with a myelomeningocele can be expected to reach their early adult years. Late deterioration is common. One of the greatest challenges in medicine today is establishing a network of care for these adults with spina bifida.

Postoperative pulmonary complications play an important role in the risk for patients undergoing noncardiothoracic surgery. Postoperative pulmonary complications are as prevalent as cardiac complications and contribute similarly to morbidity, mortality, and length of stay. Pulmonary complications may even be more likely than cardiac complications to predict long-term mortality after surgery. The purpose of this guideline is to provide guidance to clinicians on clinical and laboratory predictors of perioperative pulmonary risk before noncardiothoracic surgery. It also evaluates strategies to reduce the perioperative pulmonary risk and focuses on atelectasis, pneumonia, and respiratory failure. The target audience for this guideline is general internists or other clinicians involved in perioperative management of surgical patients. The target patient population is all adult persons undergoing noncardiothoracic surgery. *This paper, written by Amir Qaseem, MD, PhD, MHA; Vincenza Snow, MD; Nick Fitterman, MD; E. Rodney Hornbake, MD; Valerie A. Lawrence, MD; Gerald W. Smetana, MD; Kevin Weiss, MD, MPH; and Douglas K. Owens, MD, MS, was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Douglas K. Owens, MD, MS (Chair); Mark Aronson, MD; Patricia Barry, MD, MPH; Donald E. Casey Jr., MD, MPH, MBA; J. Thomas Cross Jr., MD, MPH; Nick Fitterman, MD; E. Rodney Hornbake, MD; Katherine D. Sherif, MD; and Kevin B. Weiss, MD, MPH (Immediate Past Chair). Approved by the ACP Board of Regents on 21 January 2006.

BACKGROUND: Children with the acquired immunodeficiency syndrome (AIDS) have an unusually high incidence of smooth-muscle tumors (leiomyomas and leiomyosarcomas) in addition to malignant lymphomas. We tested the hypothesis that the smooth-muscle tumors in these children are associated with the Epstein-Barr virus (EBV). METHODS: Tissue specimens of five leiomyosarcomas and two leiomyomas from six children with AIDS were studied for evidence of the human immunodeficiency virus (HIV) and EBV by in situ hybridization and quantitative polymerase chain reaction (PCR). Comparison specimens included samples of leiomyosarcoma and leiomyoma from HIV-negative children. EBV clonality of leiomyosarcomas was determined by Southern blot analysis with oligonucleotide probes for EBV terminal-repeat fragments. Tumor specimens were tested by immunoperoxidase staining for infiltration by B lymphocytes and expression of the EBV receptor. Serologic testing for EBV was performed. RESULTS: In situ hybridization showed EBV genomes in all muscle cells of the five leiomyosarcomas and the two leiomyomas from the six HIV-infected children. Quantitative PCR demonstrated strikingly high levels of EBV in tumor tissue, with as many as 4.3 genome copies per cell. Two colonic leiomyosarcomas obtained from different sites at different times from one patient contained different episomal EBV clones, signifying the presence of distinct monoclonal EBV-related tumors. We found biclonal EBV infection in the leiomyosarcoma of another patient. No EBV was detected in normal muscle or tumor specimens from HIV-negative patients. Immunostaining for the EBV receptor was strongly positive in six of the seven leiomyomas and leiomyosarcomas from the patients with AIDS. CONCLUSIONS: EBV can infect smooth-muscle cells, at least in patients with AIDS, and it may contribute to the pathogenesis of leiomyomas and leiomyosarcomas in children with AIDS. EBV seems to play no part in smooth-muscle tumors in HIV-negative children.