A phase I trial of Flavopiridol in relapsed multiple myeloma

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myelom

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Screening for adverse childhood experiences in pediatrics: A randomized trial of aggregate-level versus item-level response screening formats

BackgroundWhile there is growing support for screening for Adverse Childhood Experiences (ACEs), rigorous evidence on the efficacy and preference of screening methods is needed.ObjectiveTo examine caregiver: (1) rates of disclosure of their child's exposure to ACEs using item-level response (each item can be endorsed) versus aggregate-level response (only total score reported) screening format, (2) associations between family demographic factors and disclosure by screening format, and (3) emotional reaction and experience of screening formats in a diverse, low-income pediatric population.MethodsCaregiver participants (n = 367) were randomized to complete the Pediatric ACEs and Related Life Events Screener (PEARLS) tool, in an aggregate-level response vs item-level response format from 2016-2019. Select caregivers (n = 182) participated in debriefing interviews. T-test and chi-square analyses in 2019 compared PEARLS disclosure rates and reactions between the screening modalities. Regression models explored interactions with child characteristics. Thematic analysis of interview notes captured caregiver screening experience.ResultsPEARLS disclosure rates were significantly higher in the aggregate-level response compared to the item-level response screening arm (p <0.05). This difference was accentuated for children identified as black and/or male (p <0.05). Caregiver reactions to PEARLS screening were rarely negative in either screening format. Qualitative data demonstrated strong caregiver preference for the item-level response format; additional themes include provider relationship, fear with disclosure, and screening outcome expectations.ConclusionWhile caregivers reported a preference for the item-level response format, the aggregate-level response screening format elicited higher disclosures rates particularly for children who are black or ma.Trial registrationClinical trial registry: NCT04182906

Development and implementation of a pediatric adverse childhood experiences (ACEs) and other determinants of health questionnaire in the pediatric medical home: A pilot study.

Adverse Childhood Experiences (ACEs) are associated with poor health outcomes, underlining the significance of early identification and intervention. Currently, there is no validated tool to screen for ACEs exposure in childhood. To fill this gap, we designed and implemented a pediatric ACEs questionnaire in an urban pediatric Primary Care Clinic. Questionnaire items were selected and modified based on literature review of existing childhood adversity tools. Children twelve years and under were screened via caregiver report, using the developed instrument. Cognitive interviews were conducted with caregivers, health providers, and clinic staff to assess item interpretation, clarity, and English/Spanish language equivalency. Using a rapid cycle assessment, information gained from the interviews were used to iteratively change the instrument. Additional questions assessed acceptability of screening within primary care and preferences around administration. Twenty-eight (28) caregivers were administered the questionnaire. Cognitive interviews conducted among caregivers and among 16 health providers and clinic staff resulted in the changes in wording and addition of examples in the items to increase face validity. In the final instrument, no new items were added; however, two items were merged and one item was split into three separate items. While there was a high level of acceptability of the overall questionnaire, some caregivers reported discomfort with the sexual abuse, separation from caregiver, and community violence items. Preference for methods of administration were split between tablet and paper formats. The final Pediatric ACE and other Determinants of Health Questionnaire is a 17-item instrument with high face validity and acceptability for use within primary care settings. Further evaluation on the reliability and construct validity of the instrument is being conducted prior to wide implementation in pediatric practice

Development and implementation of a pediatric adverse childhood experiences (ACEs) and other determinants of health questionnaire in the pediatric medical home: A pilot study.

Adverse Childhood Experiences (ACEs) are associated with poor health outcomes, underlining the significance of early identification and intervention. Currently, there is no validated tool to screen for ACEs exposure in childhood. To fill this gap, we designed and implemented a pediatric ACEs questionnaire in an urban pediatric Primary Care Clinic. Questionnaire items were selected and modified based on literature review of existing childhood adversity tools. Children twelve years and under were screened via caregiver report, using the developed instrument. Cognitive interviews were conducted with caregivers, health providers, and clinic staff to assess item interpretation, clarity, and English/Spanish language equivalency. Using a rapid cycle assessment, information gained from the interviews were used to iteratively change the instrument. Additional questions assessed acceptability of screening within primary care and preferences around administration. Twenty-eight (28) caregivers were administered the questionnaire. Cognitive interviews conducted among caregivers and among 16 health providers and clinic staff resulted in the changes in wording and addition of examples in the items to increase face validity. In the final instrument, no new items were added; however, two items were merged and one item was split into three separate items. While there was a high level of acceptability of the overall questionnaire, some caregivers reported discomfort with the sexual abuse, separation from caregiver, and community violence items. Preference for methods of administration were split between tablet and paper formats. The final Pediatric ACE and other Determinants of Health Questionnaire is a 17-item instrument with high face validity and acceptability for use within primary care settings. Further evaluation on the reliability and construct validity of the instrument is being conducted prior to wide implementation in pediatric practice

Pediatric ACEs and related life event screener (PEARLS) latent domains and child health in a safety-net primary care practice.

BACKGROUND: Research examining the connections between individual adverse childhood experiences (ACEs) and how groupings of interrelated adversities are linked with subsequent health is scarce, limiting our understanding of risk during a period of rapid expansion of ACE screening in clinical practice. The study objective was to conduct a psychometric analysis to derive latent domains of ACEs and related life events and assess the association between each domain and health outcome. METHODS: Participants (3 months-11 years) were recruited from the University of California San Francisco Benioffs Children Hospital Oakland Primary Care Clinic. Children were screened with the Pediatric ACEs and Related Life Events Screener (PEARLS) (n = 340), which assessed 17 total ACEs and related life events, including forms of abuse, household challenges, and social risks. Domains were constructed using confirmatory factor analysis and associations between the three identified domains and 14 health outcomes were assessed using multivariable linear and logistic regression models. RESULTS: Three PEARLS domains were identified: Maltreatment (ω = 0.73, ɑ=0.87), Household Challenges (ω = 0.70, ɑ=0.82), and Social Context (ω = 0.55, ɑ=0.70). Measurement invariance was supported across both gender and screening format. All domains were associated with poorer general and behavioral health and stomachaches. Maltreatment and Social Context were additionally associated with eczema while only Social Context was associated with increased odds of reporting headaches and somatic symptoms. CONCLUSION: In an underserved, urban west-coast pediatric population, the PEARLS found three adversity domains of Maltreatment, Household Challenges, and Social Context that all had an independent statistically significant association with poorer child health. The results provide a timely and more nuanced representation of risk that can inform clinical practice and policy using more targeted resources and interventions

Pediatric ACEs and related life event screener (PEARLS) latent domains and child health in a safety-net primary care practice

Abstract Background Research examining the connections between individual adverse childhood experiences (ACEs) and how groupings of interrelated adversities are linked with subsequent health is scarce, limiting our understanding of risk during a period of rapid expansion of ACE screening in clinical practice. The study objective was to conduct a psychometric analysis to derive latent domains of ACEs and related life events and assess the association between each domain and health outcome. Methods Participants (3 months-11 years) were recruited from the University of California San Francisco Benioff’s Children Hospital Oakland Primary Care Clinic. Children were screened with the Pediatric ACEs and Related Life Events Screener (PEARLS) (n = 340), which assessed 17 total ACEs and related life events, including forms of abuse, household challenges, and social risks. Domains were constructed using confirmatory factor analysis and associations between the three identified domains and 14 health outcomes were assessed using multivariable linear and logistic regression models. Results Three PEARLS domains were identified: Maltreatment (ω = 0.73, ɑ=0.87), Household Challenges (ω = 0.70, ɑ=0.82), and Social Context (ω = 0.55, ɑ=0.70). Measurement invariance was supported across both gender and screening format. All domains were associated with poorer general and behavioral health and stomachaches. Maltreatment and Social Context were additionally associated with eczema while only Social Context was associated with increased odds of reporting headaches and somatic symptoms. Conclusion In an underserved, urban west-coast pediatric population, the PEARLS found three adversity domains of Maltreatment, Household Challenges, and Social Context that all had an independent statistically significant association with poorer child health. The results provide a timely and more nuanced representation of risk that can inform clinical practice and policy using more targeted resources and interventions

Pediatrics adverse childhood experiences and related life events screener (PEARLS) and health in a safety-net practice

BackgroundAdverse Childhood Experiences (ACEs) are associated with behavioral, mental, and clinical outcomes in children. Tools that are easy to incorporate into pediatric practice, effectively screen for adversities, and identify children at high risk for poor outcomes are lacking.ObjectiveTo examine the relationship between caregiver-reported child ACEs and related life events with health outcomes.Participants and settingParticipants (0-11 years) were recruited from the University of California San Francisco Benioff's Children Hospital Oakland Primary Care Clinic. There were 367 participants randomized.MethodsParticipants were randomized 1:1:1 to item-level (item response), aggregate-level (total number of exposures), or no screening for ACEs (control arm) with the PEdiatric ACEs and Related Life Event Screener (PEARLS). We assessed 10 ACE categories capturing abuse, neglect, and household challenges, as well as 7 additional categories. Multivariable regression models were conducted.ResultsParticipants reported a median of 2 (IQR 1-5) adversities with 76 % (n = 279) reporting at least one adversity; participants in the aggregate-level screening arm, on average, disclosed 1 additional adversity compared to item-level screening (p = 0.01). Higher PEARLS scores were associated with poorer perceived child general health (adjusted B = -0.94, 95 %CI: -1.26, -0.62) and Global Executive Functioning (adjusted B = 1.99, 95 %CI: 1.51, 2.46), and greater odds of stomachaches (aOR 1.14; 95 %CI: 1.04-1.25) and asthma (aOR 1.08; 95 %CI 1.00, 1.17). Associations did not differ by screening arm.ConclusionIn a high-risk pediatric population, ACEs and other childhood adversities remain an independent predictor of poor health. Increased efforts to screen and address early-life adversity are necessary

Disclosure of adversities by PEARLS screening group.

Disclosure of adversities by PEARLS screening group.</p