Mt. Washington Pediatric Hospital

Acute diarrhoea is a serious cause of infant morbidity and mortality, and the development of preventive measures remains an important goal. Bifidobacteria (which constitute the predominant intestinal flora of breastfed infants), as well as other lactic-acid-producing organisms such as Streptococcus thermophilus, are thought to have a protective effect against acute diarrhoeal disease. However, their efficacy has not been assessed in controlled trials. In a double-blind, placebo-controlled trial, infants aged 5-24 months who were admitted to a chronic medical care hospital were randomised to receive a standard infant formula or the same formula supplemented with Bifidobacterium bifidum and S thermophilus. Patients were evaluated daily for occurrence of diarrhoea, and faecal samples, obtained weekly, were analysed for rotavirus antigen by enzyme immunoassay. Faecal samples were also obtained during an episode of diarrhoea for virological and bacteriological analyses. 55 subjects were evaluated for a total of 4447 patient-days during 17 months. 8 (31%) of the 26 patients who received the control formula and 2 (7%) of 29 who received the supplemented formula developed diarrhoea during the course of the study (p = 0.035, Fisher's exact test, two-tailed). 10 (39%) of the subjects who received the control formula and 3 (10%) of those who received the supplemented formula shed rotavirus at some time during the study (p = 0.025). The supplementation of infant formula with B bifidum and S thermophilus can reduce the incidence of acute diarrhoea and rotavirus shedding in infants admitted to hospital.

INTRODUCTION: The purpose of this study was to develop an evidence-based guideline for the use of neuromuscular ultrasound in the diagnosis of carpal tunnel syndrome (CTS). METHODS: Two questions were asked: (1) What is the accuracy of median nerve cross-sectional area enlargement as measured with ultrasound for the diagnosis of CTS? (2) What added value, if any, does neuromuscular ultrasound provide over electrodiagnostic studies alone for the diagnosis of CTS? A systematic review was performed, and studies were classified according to American Academy of Neurology criteria for rating articles of diagnostic accuracy (question 1) and for screening articles (question 2). RESULTS: Neuromuscular ultrasound measurement of median nerve cross-sectional area at the wrist is accurate and may be offered as a diagnostic test for CTS (Level A). Neuromuscular ultrasound probably adds value to electrodiagnostic studies when diagnosing CTS and should be considered in screening for structural abnormalities at the wrist in those with CTS (Level B).

Chronic abdominal pain, defined as long-lasting intermittent or constant abdominal pain, is a common pediatric problem encountered by primary care physicians, medical subspecialists and surgical specialists. Chronic abdominal pain in children is usually functional-that is, without objective evidence of an underlying organic disorder. The Subcommittee on Chronic Abdominal Pain of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has prepared this report based on a comprehensive, systematic review and rating of the medical literature. This report accompanies a clinical report based on the literature review and expert opinion. The subcommittee examined the diagnostic and therapeutic value of a medical and psychologic history, diagnostic tests, and pharmacological and behavioral therapy. The presence of alarm symptoms or signs (such as weight loss, gastrointestinal bleeding, persistent fever, chronic severe diarrhea and significant vomiting) is associated with a higher prevalence of organic disease. There was insufficient evidence to state that the nature of the abdominal pain or the presence of associated symptoms (such as anorexia, nausea, headache and joint pain) can discriminate between functional and organic disorders. Although children with chronic abdominal pain and their parents are more often anxious or depressed, the presence of anxiety, depression, behavior problems or recent negative life events does not distinguish between functional and organic abdominal pain. Most children who are brought to the primary care physician's office for chronic abdominal pain are unlikely to require diagnostic testing. Pediatric studies of therapeutic interventions were examined and found to be limited or inconclusive.

OBJECTIVE: To determine if oral clonidine would reduce the duration of opioid detoxification for neonatal abstinence syndrome. METHODS: Infants with intrauterine exposure to methadone or heroin and neonatal abstinence syndrome (2 consecutive modified Finnegan scores of > or =9) were enrolled at 2 hospitals during 2002-2005 and followed until final hospital discharge. All enrolled infants (80) received oral diluted tincture of opium according to a standardized algorithm and were randomly assigned to receive oral clonidine (1 microg/kg every 4 hours) (40 infants) or placebo (40 infants). Primary outcome was duration of opioid therapy. Secondary outcomes included the amount of opium required to control symptoms, number of treatment failures, and differences in blood pressure, heart rate, and oxygen saturation. RESULTS: The median length of therapy was 27% shorter in the clonidine group (11 [95% confidence interval: 8-15 days]) than in the placebo group (15 days [95% confidence interval: 12-17 days]). In the clonidine group, 7 infants required restarting opium after initial discontinuation versus none in the placebo group, with the total length of treatment/observation remaining significantly less in the clonidine group. Higher dosages of opium were required by 40% of the infants in the placebo group versus 20% in the clonidine group. Treatment failures occurred in 12.5% of the infants in the placebo group versus none in the clonidine group. Hypertension, hypotension, bradycardia, or desaturations did not occur in either group. Three infants in the clonidine group died as a result of myocarditis, sudden infant death syndrome, and homicide, all after hospital discharge and before 6 months of age. CONCLUSIONS: In this randomized, double-blind trial, adding clonidine to standard opioid therapy for detoxification from in utero exposure to methadone or heroin reduced the duration of pharmacotherapy for neonatal abstinence without causing short-term adverse cardiovascular outcomes. A larger trial is indicated to determine long-term safety.

Abstract Purpose: Microsatellite instability (MSI) and high tumor mutation burden (TMB-High) are promising pan-tumor biomarkers used to select patients for treatment with immune checkpoint blockade; however, real-time sequencing of unresectable or metastatic solid tumors is often challenging. We report a noninvasive approach for detection of MSI and TMB-High in the circulation of patients. Experimental Design: We developed an approach that utilized a hybrid-capture–based 98-kb pan-cancer gene panel, including targeted microsatellite regions. A multifactorial error correction method and a novel peak-finding algorithm were established to identify rare MSI frameshift alleles in cell-free DNA (cfDNA). Results: Through analysis of cfDNA derived from a combination of healthy donors and patients with metastatic cancer, the error correction and peak-finding approaches produced a specificity of >99% (n = 163) and sensitivities of 78% (n = 23) and 67% (n = 15), respectively, for MSI and TMB-High. For patients treated with PD-1 blockade, we demonstrated that MSI and TMB-High in pretreatment plasma predicted progression-free survival (hazard ratios: 0.21 and 0.23, P = 0.001 and 0.003, respectively). In addition, we analyzed cfDNA from longitudinally collected plasma samples obtained during therapy to identify patients who achieved durable response to PD-1 blockade. Conclusions: These analyses demonstrate the feasibility of noninvasive pan-cancer screening and monitoring of patients who exhibit MSI or TMB-High and have a high likelihood of responding to immune checkpoint blockade. See related commentary by Wang and Ajani, p. 6887

The American Cancer Society publishes nutrition guidelines to advise the public about dietary practices that reduce cancer risk.1 These guidelines are developed by expert advisory committees and are based on existing scientific evidence that relates diet and nutrition to cancer risk in human population studies as well as in laboratory experiments. This evidence suggests that about one third of the 500,000 cancer deaths that occur in the United States each year is due to dietary factors. Another third is due to cigarette smoking. Therefore, for the large majority of Americans who do not smoke cigarettes, dietary choices and physical activity become the most important modifiable determinants of cancer risk.2 The evidence also indicates that although genetics is a factor in the development of cancer, cancer cannot be explained by heredity alone. Behavioral factors such as cigarette smoking, dietary choices, and physical activity modify the risk of cancer at all stages of its development. The introduction of healthful diet and exercise practices at any time from childhood to old age can promote health and reduce cancer risk. On the basis of its review of the scientific evidence, the American Cancer Society 1996 Advisory Committee on Diet, Nutrition, and Cancer Prevention reaffirms previous conclusions of the Society that dietary practices and physical activity—along with smoking cessation, avoidance of occupational carcinogens, and early detection—are important factors in the prevention of cancer and cancer death. Many dietary factors can affect cancer risk: types of foods, food preparation methods, portion sizes, food variety, and overall caloric balance. Cancer risk can be reduced by an overall dietary pattern that includes a high proportion of plant foods (fruits, vegetables, grains, and beans); limited amounts of meat, dairy, and other high-fat foods; and a balance of caloric intake and physical activity. Many Americans do not follow such healthful practices. Indeed, trends indicate an increase in caloric intake, greater use of high-fat convenience foods, and a decline in physical activity among Americans.3 We believe that such unhealthful trends are due in part to shifts toward consumption of food outside the home, to more sedentary lifestyle patterns, and to the advertising and promotion of high-calorie foods.4 The committee is especially concerned about the effects of such trends on the long-term health of children, who are establishing lifetime patterns of food intake and physical activity.5 In this report, the committee presents four broad guidelines to reduce cancer risk among people aged two years and older (Table 1). In addition, we offer advice on a wide variety of questions about nutrition and cancer that concern the public at large. These recommendations represent the committee's best efforts to provide advice based on scientific studies related specifically to the primary prevention of cancer. This advice does not apply to cancer treatment or to reducing the risk of cancer recurrence. The committee's recommendations are consistent in principle with the 1992 Food Guide Pyramid,6 the 1995 Dietary Guidelines for Americans,7 and dietary recommendations of other agencies for general health promotion and for the prevention of coronary heart disease, diabetes, and other diet-related chronic conditions.8-11 Although the committee recognizes that no diet can guarantee full protection against any disease, we believe that our recommendations offer the best nutrition information currently available to help Americans reduce their risk of cancer. The evidence is particularly strong that increased consumption of fruits and vegetables reduces the risk of colon cancer. Include fruits or vegetables in every meal. Choose fruits and vegetables for snacks. Include grain products in every meal. Choose whole grains in preference to processed (refined) grains. Choose beans as an alternative to meat. The scientific basis for these recommendations is very strong for cancers at many sites, particularly for cancers of the gastrointestinal and respiratory tracts.12-15 The evidence is particularly strong that increased consumption of fruits and vegetables reduces the risk of colon cancer.16 Evidence is less strong for cancers considered hormonal, such as breast and prostate cancer. Of the many scientific studies on this subject, the great majority show that eating fruits and vegetables (especially green and dark yellow vegetables and those in the cabbage family, soy products, and legumes) protects against colon cancer. Greater consumption of vegetables, fruits, or both together has also been associated with a lower risk of lung cancer.17 The major risk factor for lung cancer is tobacco, but diet also affects risk. Studies have shown that people who smoke cigarettes tend to eat less healthful diets than nonsmokers, but fruits and vegetables reduce cancer risk whether or not people smoke. Because many studies indicate that foods high in beta carotene protect against lung cancer, scientists have suggested that beta carotene itself might reduce lung cancer risk. Recent clinical trials of beta carotene supplements, however, have shown that smokers taking the supplement developed lung cancer at higher rates than those taking a placebo.18, 19 These findings support the idea that beta carotene may be a proxy for other protective nutrients or substances, singly or in combination, within foods. They also suggest that taking a single nutrient in large amounts may produce adverse effects. Despite the strength of the evidence associating consumption of fruits and vegetables with decreased cancer risk, intake of these foods is low among many adults and children.20 Concern about low intake levels has led to a country-wide initiative—the National 5 A Day for Better Health Program—to increase fruit and vegetable intake to five or more servings of fruits and vegetables daily.21 This recommendation applies to foods in their fresh, frozen, canned, dried, or juice forms, but does not apply to specific nutrients or other substances that might be extracted from them. Vegetables and fruits are complex foods containing more than 100 beneficial vitamins, minerals, fiber, and other substances. Scientists do not yet know which of the nutrients or other substances in fruits and vegetables may be protective against cancer. The principal possibilities include specific vitamins and minerals, fiber, and phytochemicals—carotenoids, flavonoids, terpenes, sterols, indoles, and phenols—that are present in foods of plant origin.12, 14 How fruits and vegetables exert their protective effects constitutes an active area of scientific inquiry. Until more is known about specific food components, the best advice is to eat 5 or more servings of fruits and vegetables each day. Grains such as wheat, rice, oats, barley, and the foods made from them constitute the base of healthful diets as illustrated in the Food Guide Pyramid.6 Healthful diets contain six to 11 standard servings of foods from this group each day. As shown in Table 2, standard portion sizes are defined as quite small, and this number of servings is not difficult to achieve. Grains are an important source of many vitamins and minerals such as folate, calcium, and selenium, all of which have been associated with a lower risk of colon cancer.16 Whole grains are higher in fiber and certain vitamins and minerals than refined flour products. Because the benefits of grain foods may derive from their other nutrients as well as from fiber,22 it is best to obtain fiber from fruits, vegetables, and whole grains rather than from fiber supplements. Beans are excellent sources of many vitamins and minerals, protein, and fiber. Beans are legumes, the technical term for the family of plants that includes dried beans, pinto beans, lentils, and soybeans, among many others. Beans are especially rich in nutrients that may protect against cancer23 and can be a useful low-fat but high-protein alternative to meat. Replace fat-rich foods with fruits, vegetables, grains, and beans. Eat smaller portions of high-fat foods. Choose baked and broiled foods instead of fried foods. Select non-fat and low-fat milk and dairy products. When you eat packaged, snack, convenience, and restaurant foods, choose those low in fat. When you eat meat, select lean cuts. Eat smaller portions of meats. Choose beans, seafood, and poultry as an alternative to beef, pork, and lamb. Select baked and broiled meats, seafood, and poultry, rather than fried. High-fat diets have been associated with an increase in the risk of cancers of the colon and rectum,16 prostate,24 and endometrium.25 The association between high-fat diets and breast cancer is much weaker.26 Whether these associations are due to the total amount of fat, the particular type of fat (saturated, monounsaturated, or polyunsaturated), the calories contributed by fat, or some other factor in food fats has not yet been determined. Because a gram of fat contains more than twice the calories of a gram of protein or carbohydrate (9 versus 4 kcal/gram), studies cannot easily distinguish the effects of fat itself from effects of the calories it contains. Moreover, people who eat high-fat diets tend to be heavier and to eat more and fruits and vegetables, their risk of cancer also is increased for other from sources major of total fat, fat, and in the American Although are sources of protein and many important vitamins and minerals, consumption of pork, been to cancers at sites, most colon and How much of the association between and cancer is due to total fat or fat, and much is due to other of or the diet is at in to fat, such as which are protein is may help the association between and colon cancer. monounsaturated, and fats all the number of but may affect cancer risk in the effects of specific such as those from vegetable or may in their effects on cancer risk. This of types of fat to cancer risk is active High-fat diets have been associated with an increase in the risk of cancers of the colon and and evidence indicates that fat may be particularly important in the risk for cancer as well as for heart The best to reduce fat intake is to choices in the and preparation of foods. Choose lean and dairy products, and vegetable for or Food can be a useful to foods lower in fat. Choose smaller portions and use as a rather than as the of a meal. beans, grains, and vegetables in to help dietary patterns to include more foods from plant rather than are also and foods, rather than reduces the overall amount of fat in These recommendations for cancer prevention are consistent with dietary advice to reduce at active for or more on most of the within activity can help protect against some by caloric intake with or by other of caloric intake and can to and increased risk for cancers at colon and rectum,16 prostate,24 breast and These findings are by and by studies an association between physical activity and a reduced risk of some may or it may in other to reduce cancer risk. breast and prostate cancer, physical activity may effects on colon cancer, physical activity the reducing the of time that the is to physical activity and caloric intake are to or to a The for and of all a within to reduce the risk for chronic such as coronary heart and as well as cancer. physical activity may increase caloric and people to more healthful fruits, vegetables, grains, and a The for and Prevention and the American of a National of Health and the of physical activity each as a to promote The does not to be to be and can be by for about two or by a variety of other and at a of to Studies suggest that people reduce their cancer caloric intake and increase physical activity. The to calories is to sizes, particularly of high-fat foods (Table is important to however, that many foods, and and other high in with cigarette smoking and use of and tobacco, cancers of the and Cancer risk with the amount of and may to with intake of as as two A is defined as of 5 of and of for and of all The higher apply to who have more and use this in and the of the the to the it with the to in The of within a that indicates whether is or is or and cancers are much more in consumption is The use of and to increased risk of and The of and is greater than the of their Studies also have an association between consumption and an increased risk of breast cancer. The for this is but the association may be due to of or its to in levels of such as or to some other may have effects on cancer risk. calories but people who may be for foods. of the studies suggest that the risk of breast cancer may increase with an intake of a intake of has been shown to the risk of coronary heart disease, at in These benefits may the risk of cancer in older than years and in older than health advise people who to their intake to two a for and one for less well than as a of smaller and greater to with an high risk for breast cancer might from and and people taking certain also from cancer is the for cancer among American and is to lung cancer in cancer cancer is by factors that affect levels age at number of breast and physical activity. Many studies suggest that may increase the risk of breast in studies suggest that diets high in fruits and vegetables the risk of breast cancer, although this evidence is much than that for other cancer the present the best advice to reduce the risk of breast cancer is to intake of eat a diet rich in fruits and vegetables, be and cancers are the of cancer among high in foods from plant sources fruits, whole grains, have been associated with a decreased risk, diets high in fat and have been associated with an increased risk of cancer. and physical also to increase risk. the best to reducing the risk of cancer is to high-fat foods, intake of meats, eat more vegetables, fruits, and whole grains, be and Studies of cancer that risk. The association may be due to the increase in levels that among who are reduce the risk of cancer, a physical activity and food cancer is the of cancer among than of lung cancer occur as a of smoking. Many studies have that the risk of lung cancer among both smokers and is lower among people who amounts of fruits and reduce the risk of lung cancer, do not smoke tobacco, and eat at five servings of vegetables and fruits every cigarettes, tobacco, and singly and increase the risk of cancers of the and amounts of fruits and vegetables that risk. protect against these do not use in any do not more than one or two each and eat at five servings of fruits and vegetables each cancer is the cancer among American Scientists know that prostate cancer is related to but are as to the of fat, meats, and dairy products has been to be associated with an increase in the risk of prostate cancer, a for reduce the risk of prostate cancer, intake of foods from especially fats and meats. The of cancer is especially in the United consumption of foods, and other in have reduce risk. with the may increase risk. reduce the risk of cancer, eat at five servings of fruits and vegetables each Because people are in the of specific foods or nutrients to specific in this area is one is the on any subject, and it is to become by may to be and be considered in the of existing but in cannot findings in The best advice is to use it is to diet based on a single or report, especially the are as are and do have to do with nutrients in fruits and vegetables to protect the against the to that as a of Because such is associated with increased cancer risk, nutrients are to protect against nutrients include selenium, and Studies suggest that people who eat more fruits and vegetables containing these have a lower risk for studies of supplements, however, have not a in cancer risk years on suggested that might cancer. however, studies of and have shown no increased risk of cancer from or beta carotene reduce cancer Because beta an is in fruits and vegetables, and eating fruits and vegetables is associated with a reduced risk of cancer, it that taking high of beta carotene might reduce cancer risk. In major people high of beta carotene in an to lung and other of these studies beta carotene to be associated with a higher risk of lung cancer in cigarette 19 and a third from beta carotene has not the beneficial effects of fruits and vegetables by of beta cigarette such may be are foods, and are made of or have been by the of from plants or other to increase to to or to nutrient or other such foods have as yet been is no to believe that these foods increase or cancer risk. related to has suggested that foods high in might help reduce the risk of cancer, but this is not Whether or not intake affects cancer risk, eating foods containing this is important to reduce the risk of and non-fat dairy products are excellent sources of calcium, as are some vegetables and beans. are and do reduce cancer are a group of in fruits and vegetables that include beta and many other of foods containing is associated with a reduced cancer risk in the diet increase cancer in the diet from foods from dairy, and evidence is available to whether dietary itself or the foods containing this might be for the increase in cancer risk associated with eating foods from has been to be more in people with cancer, but is an of cancer, not its is no evidence that an increase in cancer risk. years a suggested that might increase risk for cancer of the Because may of breast in some also have on about and breast cancer. Many studies in however, have no at all between and the risk of or any other type of cancer. affect cancer is to in meat. some suggests that or at very high that might increase cancer risk. by smoke also their of Although these cancer in it is whether cancer in such as and do not produce these are vegetables and are important in vegetables to the cabbage family, which includes and These vegetables contain certain to reduce the risk of cancer. The best evidence suggests that a wide variety of vegetables, and other vegetables, reduces cancer risk is dietary fiber and can it Dietary fiber includes a wide variety of plant that are not by of fiber are and fiber is to help reduce the risk of cancer, although the of this is fiber to reduce to lower the risk of coronary heart sources of fiber are beans, vegetables, whole grains, and eating protect against all are high in fats are rich in Studies in have that cancer but is no evidence for protective effects in at this has the effects of as or to public or foods. do not increase cancer risk. is and can it or is a in many vegetables, beans, fruits, whole grains, and may reduce the risk of some are for who are of as a to reduce the risk of and other in their evidence suggests that to reduce cancer risk, is best with the full of nutrients in fruits, vegetables, and other foods. food Many substances are to foods to them and to and are present in very in and no evidence that any at these levels human The health benefits of the in and other vegetables in the family have been is currently for its to reduce cancer risk, but evidence a specific for this vegetable in cancer our cancer risk, can diet help that increase or cancer risk can be or by and factors in the diet can protect from and can or the development of cancer in people with an increased risk for the are foods and do foods is to on foods as to their does not in the foods and is no evidence that foods cancer risk. meats, and are with to and to with can be to in the which may increase the risk of cancer. and related are to foods to this high in fruits and vegetables that contain and such as the of to in foods are not a of cancer among and factors in the diet can protect from and can or the development of cancer. is and is it related to fat are not by the Although fat are development for use in the food one of this been for may reduce fat intake, but it also reduces the of and other in fruits and Although reducing of these substances might also reduce the health benefits of fruits and vegetables, the overall of this type of fat on cancer risk is at affect cancer all is high in but its fat is of is not associated with any increase in risk of cancer, and most is with to cancer and on fruits and vegetables and can be in high Although fruits and vegetables contain low levels of these scientific evidence the overall health benefits and effects of eating fruits and In evidence is to in foods with an increased risk of any cancer. are and do reduce cancer The term to a wide variety of by of these protect plants against or have other important have or both in plants and in people who eat them. Because consumption of fruits and vegetables reduces cancer risk, are for specific in these foods that might for the beneficial effects. is no evidence that taking is as beneficial as the fruits, vegetables, beans, and grains from which are high levels of in the diet increase cancer evidence diets containing large amounts of foods by and with an increased risk of cancers of the and evidence suggests that amounts of or foods in the diet affect cancer risk. is and can it reduce cancer is a by the as part of studies suggest that protects against cancer, but human studies are are not as is a between and products are sources of reduce cancer are an excellent source of protein and a alternative to meat. have high levels of and other that to have beneficial effects on cancers in These effects to be in lower cancer evidence a diet rich in fruits, vegetables, and other plant foods with reduced risk of cancer, but is no evidence at this time that can reduce cancer risk. 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The studies in which has been as a however, have not shown a reduced risk of lower cancer may lower the risk for coronary heart supplements, however, have not been shown to reduce cancer The American Cancer Society has a to nutrition The Society recognizes that many important questions about and cancer risk The to support nutrition in two by its and by the scientists of the Society are in which and related to cancer deaths and lifestyle among a population of more than one In addition, scientists from the United States apply for for their The Society these and to the most Studies by the Society on the effects of and exercise on cancer risk have been made by the efforts of and the of of The American Cancer Society the scientific evidence dietary practices to cancer risk and dietary guidelines based on this The Society its dietary guidelines to advise the public about related to nutrition and cancer, to and to and to and that support cancer The Society nutrition guidelines in and guidelines in in the Society the Dietary Guidelines for and nutrition as a high for the the the Society a of in cancer public and to provide advice about dietary guidelines for cancer of the 1996 advisory committee in from to review previous American Cancer Society guidelines in the of studies and in of the Dietary that of the committee on recommendations for This that The committee that the Society to support an of that and studies on the of nutrition in cancer The committee also that greater efforts of in public and agencies are to these recommendations to reduce the of cancer among of the American Cancer Society 1996 Advisory on Diet, Nutrition, and Cancer and of and Food of Health for in of of Nutrition, of of of and of Health and Cancer Prevention of Health of Cancer Prevention and National Cancer of and of Cancer of of of and Nutrition, of The of and and of and The of at of of of of Nutrition, for in the on of Cancer National for Prevention and Health for and American Cancer Society National and and

Defining the complex role of the microbiome in colorectal cancer and the discovery of novel, protumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of colorectal cancer patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and protumorigenic mucosal immune responses marked by the infiltration of activated myeloid cells and IL17-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of colorectal cancer in patients. SIGNIFICANCE: Colorectal cancer is a leading cause of cancer and cancer-related deaths worldwide, with a multifactorial etiology that likely includes procarcinogenic bacteria. Using human colon cancer specimens, culturing, and murine models, we demonstrate that chronic infection with the enteric pathogen C. difficile is a previously unrecognized contributor to colonic tumorigenesis. See related commentary by Jain and Dudeja, p. 1838. This article is highlighted in the In This Issue feature, p. 1825.

Mechanical factors related to patellofemoral pain syndrome and maltracking are poorly understood. Clinically, the Q-angle, J-sign, and lateral hypermobility commonly are used to evaluate patellar maltracking. However, these measures have yet to be correlated to specific three-dimensional patellofemoral displacements and rotations. Thus, we tested the hypotheses that increased Q-angle, lateral hypermobility, and J-sign correlate with three-dimensional patellofemoral displacements and rotations. We also determined whether multiple maltracking patterns can be discriminated, based on patellofemoral displacements and rotations. Three-dimensional patellofemoral motion data were acquired during active extension-flexion using dynamic MRI in 30 knees diagnosed with patellofemoral pain and at least one clinical sign of patellar maltracking (Q-angle, lateral hypermobility, or J-sign) and in 37 asymptomatic knees. Although the Q-angle is assumed to indicate lateral patellar subluxation, our data supported a correlation between the Q-angle and medial, not lateral, patellar displacement. We identified two distinct maltracking groups based on patellofemoral lateral-medial displacement, but the same groups could not be discriminated based on standard clinical measures (eg, Q-angle, lateral hypermobility, and J-sign). A more precise definition of abnormal three-dimensional patellofemoral motion, including identifying subgroups in the patellofemoral pain population, may allow more targeted and effective treatments.

secondary prevention E levated low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk of adverse ischemic outcomes in the early post-acute coronary syndrome (ACS) period. he EVACS trial (Evolocumab in Acute Coronary Syndrome; ClinicalTrials.gov, Unique identifier: NCT03515304) enrolled patients with non-ST-segment-elevation myocardial infarction and troponin I of 5ng/mL and randomly assigned them in a 1:1 ratio to a single dose of evolocumab SQ 420 mg or matching placebo within 24 hours of presentation. We present here the LDL-C, the primary, and other atherogenic lipid outcomes, and interpret them in the clinical context by reporting the proportion of patients in each group achieving LDL-C AHA/ACC (<70 mg/dL) and ESC (<55 mg/dL for very high risk) targets at hospital discharge and 30-day follow-up. All patients received high-intensity statins unless contraindicated and were treated in accordance with current ACS guidelines. An independent Data Safety and Monitoring Board monitored the progress of the study, which was approved by the Johns Hopkins Institutional Review Board. All participants gave informed consent.

OBJECTIVE: The purpose of this study is to evaluate two updated measures of diabetes regimen adherence. The Diabetes Self-Management Profile (DSMP) is a widely used, structured interview. Limitations include a substantial interviewer and respondent time burden and the need for well-trained interviewers to use appropriate prompts and score the open-ended responses. The Diabetes Behavior Rating Scale (DBRS) is a self-administered, fixed-choice survey. RESEARCH DESIGN AND METHODS: Both measures were administered to 146 youth with type 1 diabetes (aged 11-18 years) and their parents. Items were added to the DBRS to allow for both flexible and conventional regimens, and the DSMP was modified to use standardized wording across items, accommodate flexible regimens, and permit administration by nonmedical interviewers. RESULTS: Both measures had good evidence of internal consistency (for the DSMP: parent 0.75 and youth 0.70; for the DBRS: parent 0.84 and youth 0.84). Scores on the DSMP and the DBRS were significantly related (r = 0.72 for parents and 0.74 for youth). There was moderate agreement between parent and youth (DSMP, r = 0.51; DBRS, r = 0.48). The measures were correlated with HbA1c for both parent (DSMP, r = -0.35; DBRS, r = -0.35) and youth (DSMP, r = -0.36; DBRS, r = -0.34) reports. CONCLUSIONS: Both measures exhibit good psychometric properties and good criterion validity but varied in terms of respondent and interviewer burden, issues that should be considered in selecting assessment procedures.

BACKGROUND: Little is known about availability of services and confidential care for adolescents in primary care practices or how availability among pediatric practices compares to that among other primary care practices. The objective of this study was to assess self-reported availability of services for medically emancipated conditions and confidential care in primary care practices, to compare physician responses to those from office staff who answer appointment lines, and to compare availability in pediatric practices to other primary care practice types. METHODS: We conducted a telephone survey of randomly selected practices from the Washington, DC, metropolitan area in pediatrics (Peds), internal medicine (IM), and family medicine (FM). We asked staff who answer appointment lines about availability of services for medically emancipated conditions and confidential appointments for adolescents. Physicians received the same questions via a mail survey. Responses from office staff and physicians in the same practice were linked for comparison. RESULTS: Of 434 practices contacted by telephone, 372 (86%) responded. Of the 615 physicians surveyed from these 372 practices, 264 (43%) from 170 practices responded to the mail survey. Peds practices were less likely than FM and IM practices to offer services for medically emancipated conditions and were less likely than FM practices to offer confidential services to adolescents. Office staff and physicians from FM and IM had higher agreement compared with Peds about availability of services for medically emancipated conditions. Agreement between office staff and physicians about provision of confidential appointments to adolescents was low among all practice types. However, having a written office policy on adolescent confidentiality was significantly associated with agreement between office staff and physicians about availability of confidential services. CONCLUSIONS: Care for medically emancipated conditions and confidential services for adolescents are limited among primary care practices, especially among pediatric practices. All primary care practice types had significant disagreement between office staff and physicians about availability of confidential services to adolescents. Adolescents who call appointment lines are likely to receive inaccurate information about confidentiality policies. Establishing written office policies on adolescent confidentiality may help to improve access to confidential care for adolescents.

This article will discuss many of the key concepts regarding chemodenervation and neurolysis in the management of spasticity. Topics that will be discussed include techniques for localization, strengths and limitations of various agents (botulinum toxin, phenol, and alcohol), the value of combination therapies, and the role of nerve blocks (diagnostic and therapeutic). With advancing technology have come newer methods to improve accuracy of localization for the performance of chemodenervation and neurolysis such as electromyographic guidance, electrical stimulation, and ultrasound guidance. During the last 2 decades, the addition of botulinum toxin chemodenervation as an adjunct to traditional neurolysis, medication, and therapy modalities has expanded the field of treatment of intramuscular hyperactivity in upper motor neuron syndrome. The technique of diagnostic blocks as predictors of response and the therapeutic value of nerve blocks will be discussed.

Abstract Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApcΔ716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAFV600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAFV600ELgr5CreMin (BLM) mice, tumors have similarities to human BRAFV600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express IFNγ signatures, and are sensitive to anti–PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy. Significance: Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene–microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAFV600ELgr5CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade. This article is highlighted in the In This Issue feature, p. 1601

OBJECTIVE: To assess the social-cognitive, behavioral, and physiological outcomes of a self-management intervention for youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 81 youth with type 1 diabetes aged 11-16 years were randomized to usual care versus a "diabetes personal trainer" intervention, consisting of six self-monitoring, goal-setting, and problem-solving sessions with trained nonprofessionals. Assessments were completed at baseline and multiple follow-up intervals. A1C data were obtained from medical records. ANCOVA adjusting for age and baseline values were conducted for each outcome. RESULTS: At both short-term and 1-year follow-up, there was a trend for an overall intervention effect on A1C (short-term F = 3.71, P = 0.06; 1-year F = 3.79, P = 0.06) and a significant intervention-by-age interaction, indicating a great effect among older than younger youth (short-term F = 4.78, P = 0.03; 1-year F = 4.53, P = 0.04). Subgroup analyses demonstrated no treatment group difference among younger youth but a significant difference among the older youth. No treatment group differences in parent or youth report of adherence were observed. CONCLUSIONS: The diabetes personal trainer intervention demonstrated significant effects in A1C among middle adolescents.

BACKGROUND/OBJECTIVES: The primary goal was to determine whether repetitive functional electrical stimulation (FES) for unilateral foot drop increases tibialis anterior (TA) muscle size compared with an untreated baseline and the contralateral side in cerebral palsy (CP). Secondary goals were to determine whether positive changes in muscle size and gait, if found, accumulated during the 3 intervals during which participants used the device. FES devices differ from traditional orthoses that often restrict muscle activation and may exacerbate weakness, promote continued dependence on orthoses, or precipitate functional decline. METHODS: Participants were 14 independent ambulators with inadequate dorsiflexion in swing, with a mean age of 13.1 years, evaluated before and after the 3-month baseline, 1-month device accommodation, 3-month primary intervention, and 3-month follow-up phases. The FES device (WalkAide) stimulated the common fibular nerve to dorsiflex the ankle and evert the foot while monitoring use. TA muscle ultrasound, gait velocity, and ankle kinematic data for barefoot and device conditions are reported. RESULTS: Ultrasound measures of TA anatomic cross-sectional area and muscle thickness increased in the intervention compared with baseline and with the contralateral side and were maintained at follow-up. Maximum ankle dorsiflexion decreased at baseline but improved or was maintained during the intervention phase with and without the device, respectively. Muscle size gains were preserved at follow-up, but barefoot ankle motion returned to baseline values. CONCLUSIONS: This FES device produced evidence of use-dependent muscle plasticity in CP. Permanent improvements in voluntary ankle control after repetitive stimulation were not demonstrated.

OBJECTIVE: To describe parent/caregiver reasons for attrition from tertiary care weight management clinics/programs. STUDY DESIGN: A telephone survey was administered to 147 parents from weight management clinics/programs in the National Association of Children's Hospitals and Related Institutions' (now Children's Hospital Association's) FOCUS on a Fitter Future II collaborative. RESULTS: Scheduling, barriers to recommendation implementation, and transportation issues were endorsed by more than half of parents as having a moderate to high influence on their decision not to return. Family motivation and mismatched expectations between families and clinic/program staff were mentioned as influential by more than one-third. Only mismatched expectations correlated with patient demographics and program characteristics. [corrected]. CONCLUSIONS: Although limited by small sample size, the study found that parents who left geographically diverse weight management clinics/programs reported similar reasons for attrition. Future efforts should include offering alternative visit times, more treatment options, and financial and transportation assistance and exploring family expectations.

The prevalence of morbid obesity in adolescents is rising at an alarming rate. Comorbidities known to predispose to cardiovascular disease are increasingly being diagnosed in these children. Bariatric surgery has become an acceptable treatment alternative for morbidly obese adults, and criteria have been developed to establish center-of-excellence designation for adult bariatric surgery programs. Evidence suggests that bariatric surgical procedures are being performed with increasing numbers in adolescents. We have examined and compiled the current expert recommendations for guidelines and criteria that are needed to deliver safe and effective bariatric surgical care to adolescents.

Patellofemoral pain is widely accepted as one of the most common pathologies involving the knee, yet the etiology of this pain is still an open debate. Generalized joint laxity has been associated with patellofemoral pain, but is not often discussed as a potential source of patellar maltracking. Thus, the objective of this study was to compare the complete 6 degree of freedom patellofemoral and tibiofemoral kinematics from a group of patients diagnosed with patellofemoral pain syndrome and maltracking to those from an asymptomatic population. The following null hypotheses were tested: kinematic alterations in patellofemoral maltracking are limited to the axial plane; knee joint kinematics are the same in maltrackers with and without generalized joint laxity (defined by a clinical diagnosis of Ehlers Danlos Syndrome); and no correlations exist between tibiofemoral and patellofemoral kinematics or within patellofemoral kinematics. This study demonstrated that alterations in patellofemoral kinematics, associated with patellofemoral pain, are not limited to the axial plane, minimal correlations exist between patellofemoral and tibiofemoral kinematics, and distinct subgroups likely exist within the general population of maltrackers. Being able to identify subgroups correctly within the omnibus diagnosis of patellar maltracking is a crucial step in correctly defining the pathophysiology and the eventual treatment of these patients.

We report the phase III trial efficacy of 7-valent pneumococcal conjugate vaccine against clinical and culture proven otitis media (OM) among Navajo and White Mountain Apache infants. Efficacy was -0.4% (95% CI: -19.4 to 15.6) for clinically-diagnosed OM, 5.1% (95% CI: -51.5 to 40.6) for severe OM, and 64% (95% CI: -34% to 90%) for vaccine serotype pneumococcal OM suggesting that this vaccine is efficacious for pneumococcal OM in this high risk population.

AIM: Ankle-foot orthoses are the standard of care for foot drop in cerebral palsy (CP), but may overly constrain ankle movement and limit function in those with mild CP. Functional electrical stimulation (FES) may be a less restrictive and more effective alternative, but has rarely been used in CP. The primary objective of this study was to conduct the first trial in CP examining the acceptability and clinical effectiveness of a novel, commercially available device that delivers FES to stimulate ankle dorsiflexion. METHOD: Twenty-one individuals were enrolled (Gross Motor Function Classification System [GMFCS] levels I and II, mean age 13y 2mo). Gait analyses in FES and non-FES conditions were performed at two walking speeds over a 4 month period of device use. Measures included ankle kinematics and spatiotemporal variables. Differences between conditions were revealed using repeated measures multivariate analyses of variance. RESULTS: Nineteen individuals (nine females, 10 males; mean age 12y 11mo, range 7y 5mo to 19y 11mo; 11 at GMFCS level I, eight at level II) completed the FES intervention, with all but one choosing to continue using FES beyond that phase. Average daily use was 5.6 hours (SD 2.3). Improved dorsiflexion was observed during swing (mean and peak) and at foot-floor contact, with partial preservation of ankle plantarflexion at toe-off when using the FES at self-selected and fast walking speeds. Gait speed was unchanged. INTERPRETATION: This FES device was well accepted and effective for foot drop in those with mild gait impairments from CP.