Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.

The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.

Failure to confirm high blood pressures in pediatric care-quantifying the risks of misclassification.

Pediatric practice guidelines call for repeating an elevated office blood pressure (BP) at the same visit, but there are few data available to support this recommendation. We compared the visit results in children aged 3 to 17 years with a BP reading ≥95th percentile (n = 186 732) based on the initial BP and the mean of two BP readings, using electronic medical records from 2012-2015. Failure to repeat an initial BP reading ≥95th percentile would lead to a false "hypertensive" visit result in 54.1% of children who would require follow-up visits. After an initial visit result indicating hypertension, hypertension stage I or stage II was sustained in 2.3% and 11.3% of youth during their next visits, respectively. In conclusion, only approximately half of the pediatric patients would be correctly classified based on their initial BP. The recommendation to repeat high BP during the same visit needs to be emphasized because it saves unnecessary follow-up visits.

Prevalence of polycystic ovary syndrome in adolescents.

OBJECTIVE: To investigate the prevalence of polycystic ovary syndrome (PCOS) in adolescents and its association with obesity. DESIGN: Cross-sectional study using electronic medical records. SETTING: Not applicable. PATIENT(S): Adolescents aged 15-19 years (n = 137,502). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): PCOS diagnosed or defined according to National Institutes of Health (NIH) criteria. RESULT(S): The prevalence of a confirmed diagnosis of PCOS was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included. Compared with normal/underweight girls, the odds ratios (OR and 95% confidence interval [CI]) for confirmed PCOS diagnosis were 3.85 (3.04-4.88), 10.25 (8.16-12.84), and 23.10 (18.66-28.61) for overweight, moderately obese, and extremely obese adolescents, respectively, after adjusting for potential confounders. When adolescents with two or more supportive diagnoses were included (diagnosed and undiagnosed PCOS-NIH), the ORs (95% CI) for PCOS-NIH by weight class were significantly attenuated to 2.95 (2.53-3.44), 6.73 (5.78-7.83), and 14.65 (12.73-16.86) for overweight, moderately obese, and extremely obese adolescents, respectively. CONCLUSION(S): Overweight and obesity were associated with higher odds of PCOS in adolescents. Studies based solely on diagnosis codes may underestimate the prevalence of PCOS and overestimate the magnitude of the association between obesity and PCOS.

Associations between childhood obesity and upper and lower extremity injuries.

OBJECTIVES: To estimate the overall and age-specific associations between obesity and extremity musculoskeletal injuries and pain in children. METHODS: This cross-sectional study used information from electronic medical records of 913178 patients aged 2-19 years enrolled in an integrated health plan in the period 2007-2009. Children were classified as underweight, normal weight, overweight, or moderately/extremely obese and, using multivariable logistic regression methods, the associations between weight class and diagnosis of upper or lower extremity fractures, sprains, dislocations and pain were calculated. RESULTS: Overweight (OR 1.18, 95% CI 1.15 to 1.20), moderately obese (OR 1.24, 95% CI 1.20 to 1.27) and extremely obese (OR 1.34, 95% CI 1.30 to 1.39) children had statistically significantly higher odds of lower extremity injuries/pain compared to normal weight, adjusted for sex, age, race/ethnicity and insurance status. Age-stratified analyses yielded similar results. No consistent association was observed between body mass index and injuries/pain of the upper extremities. CONCLUSIONS: Greater body mass index is associated with increased odds of lower extremity injuries and pain issues. Because the benefits of physical activity may still outweigh the risk of injury, attention should be paid to injury prevention strategies for these children at greater risk for lower extremity injuries.

Pediatric idiopathic intracranial hypertension and extreme childhood obesity.

OBJECTIVE: To estimate the magnitude of the association between overweight, moderate, and extreme childhood obesity and the risk of idiopathic intracranial hypertension (IIH). STUDY DESIGN: Risk estimates were obtained from the Kaiser Permanente Southern California Children's Health Study (n = 913 178). Weight classes were assigned by body mass index specific for age and sex. A combination of electronic database searches followed by complete medical records review was used to identify all children diagnosed with IIH between 2006 and 2009. RESULTS: We identified 78 children with IIH, the majority of whom were girls (n = 66, 84.5%), age 11-19 (n = 66, 84.5%), non-Hispanic Whites (n = 37, 47.4%), and overweight or obese (n = 57, 73.1%). The adjusted ORs and 95% CIs of IIH with increasing weight class were 1.00, 3.56 (1.72-7.39), 6.45 (3.10-13.44), and 16.14 (8.18-31.85) for underweight/normal weight (reference category), overweight, moderately obese and extremely obese 11-19 year olds, respectively (P for trend < .001). Other independent IIH risk factors included White non-Hispanic race/ethnicity for all age groups and female sex, but only in older children. Overweight/obese children also had more IIH symptoms at onset than normal weight children. CONCLUSIONS: We found that childhood obesity is strongly associated with an increased risk of pediatric IIH in adolescents. Our findings suggest that the childhood obesity epidemic is likely to lead to increased morbidity from IIH particularly among extremely obese, White non-Hispanic teenage girls. Our findings also suggest careful screening of these at risk individuals may lead to earlier detection and opportunity for treatment of IIH.

Pediatric obesity and gallstone disease.

OBJECTIVES: The aim of the present study was to investigate the association between childhood and adolescent obesity, the risk of gallstones, and the potential effect modification by oral contraceptive use in girls. METHODS: For this population-based cross-sectional study, measured weight and height, oral contraceptive use, and diagnosis of cholelithiasis or choledocholithiasis were extracted from the electronic medical records of 510,816 patients ages 10 to 19 years enrolled in an integrated health plan, 2007-2009. RESULTS: We identified 766 patients with gallstones. The adjusted odds ratios (95% CI) of gallstones for under-/normal-weight (reference), overweight, moderate obesity, and extreme obesity in boys were 1.00, 1.46 (0.94%-2.27%), 1.83 (1.17%-2.85%), and 3.10 (1.99%-4.83%) and in girls were 1.00, 2.73 (2.18%-3.42%), 5.75 (4.62%-7.17%), and 7.71 (6.13%-9.71%), respectively (P for interaction sex × weight class <0.001). Among girls, oral contraceptive use was associated with higher odds for gallstones (odds ratio 2.00, 95% CI 1.66%-2.40%). Girls who used oral contraceptives were at higher odds for gallstones than their counterparts in the same weight class who did not use oral contraceptives (P for interaction weight class × oral contraceptive use 0.023). CONCLUSIONS: Due to the shift toward extreme childhood obesity, especially in minority children, pediatricians can expect to face increasing numbers of children and adolescents affected by gallstone disease.

Implementation of clinical practice guidelines for pediatric weight management.

OBJECTIVE: To evaluate the effect of computer-assisted decision tools that standardize pediatric weight management in a large, integrated health care system for the diagnosis and management of child and adolescent obesity. STUDY DESIGN: This was a large scale implementation study to document the impact of the Kaiser Permanente Southern California Pediatric Weight Management Initiative. An average of 739, 816 outpatient visits per year in children and adolescents from 2007 to 2010 were analyzed. Height, weight, evidence of exercise and nutrition counseling, and diagnoses of overweight and obesity were extracted from electronic medical records. RESULTS: Before the initiative, 66% of all children and adolescents had height and weight measured. This increased to 94% in 2010 after 3 years of the initiative (P < .001). In children and adolescents who were overweight or obese, diagnosis of overweight or obesity increased significantly from 12% in 2007 to 61% in 2010 (P < .001), and documented counseling rates for exercise and nutrition increased significantly from 1% in 2007 to 50% in 2010 (P < .001). CONCLUSIONS: Computer-assisted decision tools to standardize pediatric weight management with concurrent education of pediatricians can substantially improve the identification, diagnosis, and counseling for overweight or obese children and adolescents.

Higher prevalence of obesity among children with asthma.

The aim of this study is to investigate the association between childhood obesity and asthma, and whether this relationship varies by race/ethnicity. For this population-based, cross-sectional study, measured weight and height, and asthma diagnoses were extracted from electronic medical records of 681,122 patients aged 6-19 years who were enrolled in an integrated health plan 2007-2009. Weight class was assigned based on BMI-for-age. Overall, 18.4% of youth had a history of asthma and 10.9% had current asthma. Adjusted odds of current asthma for overweight, moderately obese, and extremely obese youth relative to those of normal weight were 1.22 (95% confidence interval (CI): 1.20, 1.24), 1.37 (95% CI: 1.34, 1.40), and 1.68 (95% CI: 1.64, 1.73), respectively (P trend < 0.001). Black youth are nearly twice as likely (adjusted odds ratio (OR) = 1.93, 95% CI: 1.89, 1.99), and Hispanic youth are 25% less likely (adjusted OR = 0.75, 95% CI: 0.74, 0.77), to have current asthma than to non-Hispanic white youth. However, the relationship between BMI and asthma was strongest in Hispanic and weakest in black youth. Among youth with asthma, increasing body mass was associated with more frequent ambulatory and emergency department visits, as well as increased inhaled and oral corticosteroid use. In conclusion, overweight, moderate, and extreme obesity are associated with higher odds of asthma in children and adolescents, although the association varies widely with race/ethnicity. Increasing BMI among youth with asthma is associated with higher consumption of corticosteroids and emergency department visits.

The association of psoriasis and elevated blood lipids in overweight and obese children.

OBJECTIVE: To investigate whether obesity and cardiovascular risk factors are associated with psoriasis in children and adolescents. STUDY DESIGN: For this population-based, cross-sectional study, measured weight and height, laboratory data, and psoriasis diagnoses were extracted from electronic medical records of 710,949 patients age 2 to 19 years enrolled in an integrated health plan. Weight class was assigned on the basis of body mass index-for-age. RESULTS: The OR for psoriasis was 0.68, 1.00, 1.31, 1.39, and 1.78 (95% CI, 1.49 to 2.14) for underweight, normal-weight, overweight, moderately obese, and extremely obese children, respectively (P for trend < .001). The OR for psoriasis treated with systemic therapy or phototherapy as an indicator of severe or widespread psoriasis was 0.00, 1.00, 2.78, 2.93, and 4.19 (95% CI, 1.81 to 9.68) for underweight, normal-weight, overweight, moderately obese, and extremely obese children, respectively (P for trend < .003). In adolescents, mean total cholesterol, low-density lipoprotein cholesterol, triglycerides, and alanine aminotransferase were significantly higher in children with psoriasis compared with children without psoriasis after adjustment for body mass index. CONCLUSION: Overweight and obesity are associated with higher odds of psoriasis in youths. Independent of body weight, adolescent patients with psoriasis have higher blood lipids. These data suggest that pediatricians and dermatologists should screen youths with psoriasis for cardiovascular disease risk factors.

Low prevalence of psoriasis among children and adolescents in a large multiethnic cohort in southern California.

BACKGROUND: Little information is available on the prevalence of psoriasis in children and adolescents. OBJECTIVE: We sought to estimate the prevalence of pediatric psoriasis in southern California and to investigate the validity of psoriasis diagnosis by a dermatologist compared with a nondermatologist. METHODS: In a southern California population of 710,949 children who were enrolled in an integrated prepaid health plan in 2007 through 2008, cases of psoriasis were identified from electronic medical records and validated by medical chart review. Positive predictive values for valid diagnosis were reported for dermatologists and nondermatologists. RESULTS: The prevalence of pediatric psoriasis confirmed by medical chart review was 19/10,000 patients. The prevalence of psoriasis diagnosis (confirmed and unconfirmed) was 30/10,000 patients. The age at onset of psoriasis was slightly earlier in boys than in girls. The positive predictive value for a valid diagnosis of psoriasis was 63.7% when the diagnosis was made by any health care provider, 90.0% by a dermatologist, and 26.6% by a nondermatologist. The prevalence of psoriasis was higher in girls than in boys. Psoriasis affected 29 (95% confidence interval [CI] 27-32) non-Hispanic whites, 20 (95% CI 16-24) Asian/Pacific Islanders, 16 (95% CI 15-18) Hispanic whites, and 6 (95% CI 4-9) blacks per 10,000 patients. LIMITATIONS: Information on the age at onset was estimated based on the first documented diagnosis of psoriasis. CONCLUSION: The overall prevalence of pediatric psoriasis was lower compared with other published studies. This could be in part a result of underdiagnosis because of greater sunlight exposure in southern California and a lower proportion of non-Hispanic whites in the population.

Extreme childhood obesity is associated with increased risk for gastroesophageal reflux disease in a large population-based study.

OBJECTIVE: Gastroesophageal reflux disease (GERD) may link the obesity epidemic to an array of adverse health outcomes including chronic esophageal inflammation and, consequentially, to pathophysiological changes of the esophagus. Although obesity and GERD are associated in adults, data in children are scarce and inconclusive. The aim of this study is to investigate whether, similar to adults, obesity is associated with GERD in youth. METHODS: For this population-based, cross-sectional study, measured weight and height and diagnosis of GERD were extracted from electronic medical records of 690 321 patients, aged 2-19 years, who were enrolled in an integrated prepaid health plan between 2007 and 2008. Weight class (normal weight, overweight, moderate and extreme obesity) was assigned based on body mass index-for-age. RESULTS: Overall, GERD was diagnosed in 1.5% of boys and 1.8% of girls (P<0.001). Moderately and extremely obese children, aged 6-11 years, were more likely to have a diagnosis of GERD compared with normal weight (OR 1.16, 95% CI: 1.02-1.32 and 1.32, 95% CI: 1.13-1.56, respectively). Children aged 12-19 years showed similar associations (OR 1.16, 95% CI: 1.07-1.25 and 1.40, 95% CI: 1.28-1.52, respectively). These associations remained with adjustment for sex and race/ethnicity. By contrast, obesity was not related to increased odds for GERD in children aged 2-5 years of age. CONCLUSIONS: The association between childhood obesity and GERD may have important implications for their future risk of GERD-associated diseases, such as esophageal adenocarcinoma.

Prevalence of extreme obesity in a multiethnic cohort of children and adolescents.

OBJECTIVE: To estimate the prevalence of extreme obesity in a large, multiethnic contemporary cohort of children and adolescents. STUDY DESIGN: In a cross-sectional study, measured weight and height were extracted from electronic medical records of 710,949 patients aged 2 to 19 years (87.8% of eligible patients) who were enrolled in an integrated prepaid health plan in 2007 and 2008. Prevalence of extreme obesity was defined as body mass index (BMI)-for-age>or=1.2 times 95th percentile or BMI>or=35 kg/m2. RESULTS: Extreme obesity was observed in 7.3% of boys and 5.5% of girls. The prevalence peaked at 10 years of age in boys and at 12 years of age with a bimodal distribution in girls (second peak at 18 years; P value for sex x age interaction=.036). The prevalence of extreme obesity varied in ethnic/racial and age groups, with the highest prevalence in Hispanic boys (as high as 11.2%) and African-American girls (as high as 11.9%). CONCLUSION: Extreme obesity in Southern California youth is frequently observed at relatively young ages. The shift toward extreme body weights is likely to cause an enormous burden of adverse health outcomes once these children and adolescents grow older.

Body weight and height data in electronic medical records of children.

OBJECTIVE: Data entry errors may occur in body weights and heights assessed during routine medical care. These errors may affect data quality markedly and create a large number of biologically implausible values. To address this issue, we evaluated the quality of body weight and height measures for children based on sequential health care encounters. METHODS: We evaluated the weight and height data of children aged 0-18 years receiving care at Kaiser Permanente Southern California medical centers. Error rates were calculated before and after excluding implausible values for height and weight as recorded in the electronic medical chart reviews. RESULTS: The error rates in weight and height data of children aged <2, 2-5, 6-9, 10-13, 14-18 years were 0.4%, 0.7%, 1.0%, 1.0% and 0.7%, respectively. The most frequently identified errors were implausibly low values for height and implausibly high values for weight. After excluding implausible values, the error rates were 0.4%, 0.4%, 0.6%, 0.4% and 0.1%, respectively. The sensitivity of our approach to detect errors was 10.9%, 36.6%, 32.9%, 59.2%, and 82.5%, respectively. CONCLUSIONS: Error rates in weight and height recorded in the electronic medical record during routine medical care are low, raising the potential for this information to be used for population care management. With little effort and with the recording of this information at each encounter, error rates can be further lowered to avoid misclassification of children as obese.

Trends in nonalcoholic fatty liver disease-related hospitalizations in US children, adolescents, and young adults.

OBJECTIVE: To investigate temporal trends of nonalcoholic fatty liver disease (NAFLD) and obesity among hospitalized US children, adolescents, and young adults over the past 2 decades and to examine potential sex disparities in NAFLD hospitalizations. METHODS: Hospitalization discharges with NAFLD or obesity were identified among children and young adults (6-25 years, weighted n = 91,687,413) from the 1986 to 2006 National Hospital Discharge Survey data. Age- and sex-specific rates and trends in hospitalizations with NAFLD and obesity were estimated. Rates were standardized to age distribution of the 2000 US Census population. Sex disparities were examined for the most recent period 2004 to 2006 (weighted n = 12,969,532). RESULTS: Between 1986 to 1988 and 2004 to 2006, hospitalizations with NAFLD diagnosis increased from 0.9 to 4.3/100,000 population (P < 0.001). During the same time, hospitalizations with a diagnosis of obesity increased from 35.5 to 114.7/100,000 population (P < 0.001). During 2004 to 2006, hospitalization rates with a diagnosis of NAFLD were higher among females than among males (5.9 vs 2.7/100,000 population, P < 0.001), as were hospitalizations with a diagnosis of obesity (140.8 vs 61.5/100,000 population, P < 0.001). Obesity and diabetes were reported in 43.3% and 31.9%, respectively, of discharges with NAFLD. CONCLUSION: The prevalence of NAFLD among young hospitalized patients increased in the past 2 decades, paralleling obesity-related hospitalizations. This could be a consequence of the obesity epidemic or of increased screening for liver disease.