Long-term outcomes of lentiviral gene therapy for the ß-hemoglobinopathies: the HGB-205 trial.

Sickle cell disease (SCD) and transfusion-dependent ß-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34+ cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling ßA-T87Q-globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13-21 years, were treated after busulfan myeloablation 4.6-7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis.

BACKGROUND: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. METHODS: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. CONCLUSION: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide's overall safety.

Clinical Variability in Cardiovascular Disease Risk Factor Screening and Management in Adolescent and Young Adult Women with Polycystic Ovary Syndrome.

STUDY OBJECTIVES: To review the clinical presentation, evaluation, and management of normal-weight (NW), overweight (OW), and obese (OB) adolescent and young adult women with polycystic ovary syndrome (PCOS) during a 2-year follow-up. DESIGN: Retrospective chart review. PARTICIPANTS: One hundred seventy-three adolescent and young adult women, aged 12-22 years, diagnosed with PCOS. INTERVENTIONS: Demographic, health data, and laboratory measures were abstracted from 3 clinic visits: baseline and 1- and 2-year follow-up. Subjects were classified as NW, OW, or OB. Longitudinal data were analyzed using repeated-measures analysis of variance. MAIN OUTCOME MEASURES: Body mass index, self-reported concerns, and lifestyle changes. RESULTS: Most patients (73%) were OW or OB. Family history of type 2 diabetes was greater in OW (38%) and OB (53%) patients compared with NW (22%) patients (P = .002). Acanthosis nigricans was identified in OW (62%) and OB (21%) patients but not in NW patients (0%; P < .001). OW and OB patients had higher fasting insulin (P < .001) and lower high-density lipoprotein cholesterol (P = .005) levels than NW patients, although screening rates were low. Body mass index Z-scores decreased in both OW and OB patients over time (0.07 unit/yr, P < .001). CONCLUSIONS: Most patients with PCOS were OW or OB. Substantial clinical variability existed in cardiovascular disease (CVD) screening; among those screened, OW and OB patients had greater CVD risk factors. Despite self-reported concerns about weight and diabetes risk among OW and OB patients, no clinically significant change in body mass index percentile occurred. Evidence-based interventions and recommendations for screening tests are needed to address CVD risk in adolescents and young adults with PCOS.

School social capital and body mass index in the National Longitudinal Study of Adolescent Health.

BACKGROUND: Social capital in neighborhoods and workplaces positively affects health. Less is known about the influence of school social capital on student health outcomes, in particular weight status. We sought to examine the association between individual- and school-level social capital and student body mass index (BMI). METHODS: Analyzing data from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents in grades 7-12 (N = 13,428), we used principal components analysis to define 3 school social capital factors: "connectedness" (feel part of/close to people/safe in school), "treatment" (get along with teachers/students, teachers treat students fairly), and "parental involvement" (school administrator reported percent family/parent self-reported participation in Parent Teacher Organization, average daily school attendance). We examined the associations between individual- and school-level social capital and individual BMI using multilevel modeling techniques. RESULTS: In girls, both feeling connected to one's school (ß = -0.06, p < .05) and attending schools with overall high connectedness (b = -0.43, p < .01) were associated with lower BMIs. In boys only attending a school with high "treatment" was inversely associated with BMI (b = -0.61, p < .01), adjusting for individual and school demographics. CONCLUSIONS: Although further studies are needed, our findings suggest enhancing school social capital as a novel approach to addressing student obesity.

School programs and characteristics and their influence on student BMI: findings from healthy passages.

BACKGROUND: Little is known about the contribution of school contextual factors to individual student body mass index (BMI). We set out to determine if school characteristics/resources: (1) are associated with student BMI; (2) explain racial/ethnic disparities in student BMI; and (3) explain school-level differences in student BMI. METHODS: Using gender-stratified multi-level modeling strategies we examined the association of school characteristics/resources and individual BMI in 4,387 5(th) graders in the Healthy Passages Longitudinal Study of Adolescent Health. Additionally, we examined the association of race/ethnicity and individual BMI as well as the between-school variance in BMI before and after adding individual and school characteristics to test for attenuation. RESULTS: The school-level median household income, but not physical activity or nutrition resources, was inversely associated with female BMI (ß = -0.12, CI: -0.21,-0.02). Neither school demographics nor physical activity/nutrition resources were predictive of individual BMI in males. In Black females, school characteristics attenuated the association of race/ethnicity and BMI. Individual student characteristics-not school characteristics/resources-reduced the between-school variation in BMI in males by nearly one-third and eliminated it in females. CONCLUSIONS: In this cohort of 5(th) graders, school SES was inversely associated with female BMI while school characteristics and resources largely explained Black/White disparities in female weight status. Between-school differences in average student weight status were largely explained by the composition of the student body not by school characteristics or programming.

Real-time, contextual intervention using mobile technology to reduce marijuana use among youth: a pilot study.

We evaluated the feasibility, acceptability, and potential efficacy of MOMENT, an intervention to reduce youth marijuana use that combines brief motivational enhancement therapy with mobile self-monitoring and responsive messaging. At baseline, primary care patients ages 15-24 who used marijuana frequently (at least 3 times per week) completed a recall assessment, then 1 week of mobile momentary and daily reports on use-related factors. For the intervention, youth participated in two motivational enhancement therapy sessions, during which they identified their top-3 social and emotional triggers for use and discussed healthy ways to manage them. They then completed two weeks of mobile reports. Upon reporting a top-3 trigger for use, desire to use, or recent use, they received a message supporting self-efficacy and prompting consideration of coping strategies. Generalized estimating equations examined changes in momentary-, daily-, and individual-level measures on 3-month recall and mobile assessments. Twenty-seven youth (M=19.2 years, 70% female) enrolled; there were 377-677 momentary and 50-106 daily reports per study phase. Participants reported reading the messages and finding them motivating, being comfortable with participation, and not experiencing the study as burdensome. Although proportion of momentary reports of being in a top-3 trigger context did not change (36%-43%), marijuana desire in a top-3 trigger context and marijuana use after top-3 trigger exposure decreased over the study (p<.0001 and p=.03, respectively). Daily- and individual-level measures showed similar, non-significant, improvements. The MOMENT intervention appears feasible, well-accepted, and potentially efficacious for youth who use marijuana frequently.

Associations between affect, context, and sexual desire in depressed young women.

We investigated associations of sexual desire with time of day, physical and social context, and positive and negative affect using momentary sampling in 44 depressed young women (mean age = 18). Analyses revealed that depressed young women experienced sexual desire when with their boyfriends and later in the evening. Sexual desire was also positively associated with positive affect. Sexual desire was not associated with negative affect or physical context. This research suggests that sexual desire is experienced by depressed young women in normative developmental social contexts. Our findings may help clinicians and sexual health educators in correcting the myth that depressed women do not have sexual desire.

Middle school food environments and racial/ethnic differences in sugar-sweetened beverage consumption: findings from the Healthy Choices study.

BACKGROUND: Prior studies have demonstrated disproportionate clustering of fast food outlets around schools. PURPOSE: The purpose of this study is to determine if racial/ethnic differences in middle school student self-reported sugar-sweetened beverage (SSB) consumption is explained by differential distributions of food outlets surrounding their schools. METHODS: Baseline (2005) data were analyzed from 18,281 middle school students in 47 Massachusetts schools participating in Healthy Choices, an obesity prevention program. Linear mixed effects models were used to examine the association of individual race/ethnicity and daily SSB consumption and the potential mediating effect of the density of food outlets (the number of fast food outlets and convenience stores in a 1500 m buffer area surrounding the school) on this association adjusting for individual and school demographics. RESULTS: More SSB consumption was reported by students of all racial/ethnic minority groups compared to their White peers except Asians. The density of fast food restaurants and convenience stores was not associated with individual SSB consumption (ß=0.001, p=0.875) nor did it mediate the association of race/ethnicity and SSB consumption. CONCLUSIONS: Racial and ethnic differences in SSB consumption among MA middle school students cannot be fully explained by the location of fast food restaurants and convenience stores.

Characteristics of screen media use associated with higher BMI in young adolescents.

OBJECTIVES: This study investigates how characteristics of young adolescents' screen media use are associated with their BMI. By examining relationships between BMI and both time spent using each of 3 screen media and level of attention allocated to use, we sought to contribute to the understanding of mechanisms linking media use and obesity. METHODS: We measured heights and weights of 91 13- to 15-year-olds and calculated their BMIs. Over 1 week, participants completed a weekday and a Saturday 24-hour time-use diary in which they reported the amount of time they spent using TV, computers, and video games. Participants carried handheld computers and responded to 4 to 7 random signals per day by completing onscreen questionnaires reporting activities to which they were paying primary, secondary, and tertiary attention. RESULTS: Higher proportions of primary attention to TV were positively associated with higher BMI. The difference between 25th and 75th percentiles of attention to TV corresponded to an estimated +2.4 BMI points. Time spent watching television was unrelated to BMI. Neither duration of use nor extent of attention paid to video games or computers was associated with BMI. CONCLUSIONS: These findings support the notion that attention to TV is a key element of the increased obesity risk associated with TV viewing. Mechanisms may include the influence of TV commercials on preferences for energy-dense, nutritionally questionable foods and/or eating while distracted by TV. Interventions that interrupt these processes may be effective in decreasing obesity among screen media users.

The contribution of school environmental factors to individual and school variation in disordered weight control behaviors in a statewide sample of middle schools.

We investigated the contribution of school environmental factors to individual and school variation in disordered weight control behaviors (DWCB). Analyses were based on self-report data gathered from 18,567 middle-school students in 2005 and publicly available data on school characteristics. We observed large differences across schools in percent of students engaging in DWCB in the past month, ranging from less than 1% of the student body to 12%. School-neighborhood poverty was associated with higher odds of DWCB in boys. Preventive strategies need to account for wide variability across schools and environmental factors that may contribute to DWCB in early adolescence.

The association of adolescent socioeconomic position and adult height: variation across racial/ethnic groups.

Numerous studies have demonstrated the association of childhood socioeconomic position and adult height. Many have suggested the use of adult height as a marker of overall childhood well-being. However, few studies have examined the relationship between child/adolescent socioeconomic position and adult height in a racially/ethnically diverse cohort. Using the National Longitudinal Study of Adolescent Health, we examined the association of child/adolescent SEP (maternal education and maternal report of household income) and measured adult height in a diverse cohort of US adolescents/young adults. We found a positive gradient effect of maternal education on height in the overall population and in White and Mixed race males and females; no such gradient existed in Hispanic, Asian, or Black males or females. Only in Mixed race females was household income positively associated with height. These findings emphasize the need to recognize differential effects of socioeconomic status on height in different racial/ethnic and gender subpopulations.

Individual and contextual predictors of severity of marijuana use events among young frequent users.

This study used momentary sampling to characterize marijuana events among young frequent users and determine contextual and individual predictors of use severity. Medical clinic outpatients aged 15-24 who used marijuana at least twice a week completed a baseline assessment, then used a handheld computer to report marijuana use at 4-6 signal-prompted times per day and before/after use for 2 weeks. Reports assessed event characteristics (when, with whom, where, how, why, how much, how high). Timestamps identified time, weekend, and duration for each event. Generalized estimating equations tested associations of individual and event-specific contextual characteristics with hits/event, duration, and high. Forty-one youth completed 3868 momentary reports; 40 (98%) reported at least one marijuana use event (N=432 events; M=10.5/participant) and thus provided data for these analyses. Marijuana was most commonly used with other people (74% of events), at home (58%), via blunt (66%), and for social or enhancement reasons (86%). Most events (62%) occurred on weekdays; use was least likely in the morning (8%). Most events involved 6 or more hits (81%). Mean high was 5.2 (out of 8). Of events with start and end times (n=250), mean duration was 46.8 min. Poor mental health and use with a blunt or a bong, in the morning or evening, and on the weekend were associated with 6 or more hits/event. Female gender was associated with greater event duration. Poor mental health predicted higher high. Among youth who used it frequently, marijuana was used in a variety of contexts, with diversity in method, dose, and duration. Contextual factors appeared to predict marijuana dose for a given event, while individual characteristics were more predictive of high and duration.

Feasibility and utility of momentary sampling of sex events in young couples.

Research on couples' sexual behaviors is limited because most studies collect data from only one person, rely on retrospective recall, and lack ecological validity. This study explored the feasibility of using momentary sampling (MS) methods to collect sex event data from both members of heterosexual young adult couples. Over two weeks, 40 participants (20 couples) were asked to use a handheld computer to respond to random auditory signals each day and self-initiate a report as soon as possible after sex. Couples were randomized into two groups: (a) both partners reported after sex events, or (b) one partner reported after sex events during Week 1 and the other during Week 2 (randomized by gender). Descriptive statistics examined protocol compliance, partner agreement on whether an event occurred, condom use, and reason for sex, as well as partner involvement in reporting, comfort with reporting after sex, and study burden. Results indicated that couples were willing and able to adhere to the protocol. Partners agreed on condom use for nearly all sex events, but frequently reported different reasons for sex events. The use of MS methods to collect information about sex events within couples is a promising approach to the study of sexual behavior.

Dietary and physical activity factors related to eating disorder symptoms among middle school youth.

BACKGROUND: Dietary and physical activity (PA) behaviors can predict disordered weight control behaviors (DWCB) among youth. This study examines dietary and PA correlates of DWCB and differences by race/ethnicity and weight status in a diverse sample of youth. METHODS: Self-reported data on dietary weight management behaviors, strengthening/toning exercises, moderate-to-vigorous physical activity, and DWCB (vomiting, taking laxatives, and/or taking diet pills without a prescription) were obtained from 15,260 sixth to eighth graders in 47 middle schools participating in the Massachusetts Healthy Choices Study at baseline (2005). Generalized estimating equations were used to estimate odds of DWCB associated with dietary and PA behaviors and to examine for differences by race/ethnicity and weight status, adjusting for covariates and clustering of individuals within schools. RESULTS: Disordered weight control behaviors were reported by 3.6% of girls and 3.1% of boys. Youth who engaged in strengthening/toning exercises 7 days per week versus 0-3 days per week had increased odds of DWCB (girls odds ratio [OR] = 1.9; 95% confidence interval [CI] = 1.3 - 3.0; boys OR = 1.5; 95% CI = 1.0 - 2.2). Dietary weight management behaviors were associated with increased odds of DWCB (girls OR = 1.2; 95% CI = 1.1 - 1.3; boys OR = 1.3; 95% CI = 1.2 - 1.4) for each additional behavior. These associations did not differ by race/ethnicity or weight status. CONCLUSIONS: Persons promoting healthy dietary and PA behaviors among youth should consider the co-occurrence of strengthening/toning and dietary weight management behaviors with DWCB and the consistency in these associations across racial/ethnic and weight status groups.

The context of desire to use marijuana: momentary assessment of young people who frequently use marijuana.

Drawing on factors identified in the literature, this study explored in-the-moment associations of social, emotional, and temporal contexts and perceived marijuana availability with desire to use the drug, using momentary sampling methodology with young people who frequently use marijuana. Forty-one adolescent/young adult medical outpatients aged 15 to 24 years who reported using marijuana at least twice a week completed 2,912 brief questionnaires on a handheld computer in response to signals emitted at random four to six times a day for 2 weeks. The questionnaires assessed, for the moment when signaled, desire to use marijuana, location, companionship, perceived ease of getting marijuana (availability), positive affect, and negative affect. Participants reported any desire to use marijuana on 1,528 reports (55%). Companionship, perceived availability, and positive affect were independently associated with having any desire to use marijuana. Once desire to use marijuana was present, time of day, positive affect, and negative affect were independently associated with strength of desire. By collecting data in real time, in real life, this study highlights the importance of examining and intervening on emotional, environmental, and temporal contexts for youth who frequently use marijuana in order to reduce their desire to use the drug.

Substance use, sexual intercourse, and condom nonuse among depressed adolescents and young adults.

PURPOSE: To examine daily- and event-level associations of substance use with occurrence of sex and condom nonuse among depressed youth. METHODS: Depressed, sexually active outpatients aged 15-22 years reported alcohol use, marijuana use, and sex on a personal digital assistant for 2 weeks. If they reported sex, participants indicated partner type and condom use. Data were analyzed for participants who reported both substance use and sex events (N = 39) using generalized estimating equations. Daily-level models compared the likelihood of sex and of condom nonuse between days on which participants did or did not use substances. Event-level models examined the likelihood of sex in the 2, 6, and 12 hours after substance use and the likelihood of condom nonuse if substances were used in the preceding 2, 6, and 12 hours. RESULTS: Participants reported 307 sex events (180 unprotected) and 391 substance use events on 572 days. Substance use was associated with increased odds of sex on the same day, but not after adjusting for weekend. Depressed youth were less likely to have sex within 2 hours after substance use and more likely to have sex within 12 hours after marijuana use. There was no main effect of substance use on condom nonuse; however, there was a significant interaction such that on weekdays, condom nonuse was less likely when substances were used within 6 hours before sex. CONCLUSIONS: The findings from this small, predominantly female sample suggest that contextual factors, not intoxication, influence associations of substance use with sexual behavior in depressed youth.

Sexual orientation and bias in self-reported BMI.

Our objective was to determine if sexual orientation groups differ in accuracy of BMI (kg/m(2)) calculated from self-reported height and weight and if weight status modifies possible differences. Using gender-stratified multiple linear regression to analyze Wave III of the National Longitudinal Study of Adolescent Health (n = 12,197), we examined the association of sexual orientation with BMI calculated from self-reported height and weight (self-reported BMI), controlling for BMI calculated from objectively measured height and weight (objectively measured BMI) as well as demographic, health, and behavioral variables. We tested for effect modification of the relationship between sexual orientation and self-reported BMI by objectively measured BMI. The population underestimated their BMI (females: ß = 0.87, P < 0.001; males = 0.86, P < 0.001). Sexual orientation groups differed little in their accuracy of reporting; only gay males had significant underreporting (ß = -0.37, P = 0.038) relative to their heterosexual peers. We found no evidence of effect modification of the relationship of sexual orientation and self-reported BMI by objectively measured BMI. With the exception of gay males, sexual orientation groups are consistent in their underreporting of BMI thus providing confidence in most comparisons of weight status based on self-report. Self-reporting of weight and height by gay males may exaggerate the differences in BMI between gay and heterosexual males.

Food insecurity and increased BMI in young adult women.

Food insecurity has been associated with weight status in children and adults although results have been mixed. We aimed to identify whether food insecurity was associated with BMI in young adults and whether this association differed by gender and was modified by food stamp use and the presence of children in the home. Cross-sectional data from wave 4 (2007-2008) of the National Longitudinal Study of Adolescent Health were analyzed. Multiple linear regression was used to investigate the association between food insecurity and BMI in gender stratified models of young adult women (n = 7,116) and men (n = 6,604) controlling for age, race/ethnicity, income, education, physical activity, smoking, alcohol use, the presence of children in the home, and food stamp use in young adulthood and/or adolescence. Food insecurity was more common in young adult women (14%) than young adult men (9%). After controlling for a variety of individual variables, food insecure women had a BMI that was on average 0.9 kg/m(2) units higher than women who were food secure. This difference in BMI persisted after controlling for recent or past food stamp use and was not different among women with or without children in the household. No relationship was found between food insecurity and BMI in young adult men. Providers should inquire about food insecurity, especially when treating obesity, and policy initiatives should address the role of access to healthy food in those facing food insecurity.

The association of body mass index and externally perceived attractiveness across race/ethnicity, gender, and time.

PURPOSE: Being perceived by others as unattractive is associated with negative health and social consequences. Overweight individuals may be more likely to be perceived by others as unattractive, thereby further endangering their well-being. Our objective was to determine whether body mass index (BMI) was associated with perceptions by others regarding attractiveness and whether this relationship was similar across race/ethnicity, gender, and time. METHODS: We analyzed Waves I and III of the National Longitudinal Study of Adolescent Health, a nationally representative longitudinal study of adolescents. We used participant gender- and race/ethnicity-stratified multinomial logistic regression to examine the association between BMI and interviewer-rated attractiveness (1 = unattractive, 2 = average, 3 = attractive, 4 = very attractive) controlling for participant age, household income, and maternal education. RESULTS: BMI was positively associated with risk of being categorized as unattractive (relative to very attractive) by the interviewer in black (Wave I: relative risk ratio [RRR] = 1.26, CI: 1.18, 1.33; Wave III: RRR = 1.14, CI: 1.08, 1.20), Hispanic (Wave I: RRR = 1.23, CI: 1.11, 1.36; Wave III: RRR = 1.22, CI: 1.12, 1.34), and white (Wave I: RRR = 1.25, CI: 1.19, 1.32; Wave III: RRR = 1.22, CI: 1.17, 1.28) females in both waves of data collection. Only in African American females, the risk of being rated unattractive with increasing BMI declined significantly between waves (p = .00018). Trends were similar in males, although the magnitude of risk was smaller and nonsignificant in most groups. CONCLUSIONS: Interviewers were more likely to rate those with higher BMIs as unattractive; this finding was similar across gender and racial/ethnic groups with few exceptions and was stable across time.

Momentary affective states surrounding sexual intercourse in depressed adolescents and young adults.

Depressed young people may have sexual intercourse (sex) to regulate their disordered affective states. This study sought to determine how momentary positive and negative affect relate to subsequent sex events in depressed adolescents and young adults. Fifty-four outpatients (87% female) 15-22 years who reported clinically significant depressive symptoms and having sex at least once a week completed a baseline survey, then reported momentary affective states and the occurrence of sex events on a handheld computer in response to 4-6 random signals per day for 2 weeks. Participants identified 387 unique sex events (median, 3.5/participant/week) on 3,159 reports (median, signal response rate 80%). Most (86-96%) reported low burden of participation on questions asked at study completion. Similar to what has been reported in non-depressed young people, momentary positive and negative affect were both improved beginning approximately 6 h before until approximately 6 h after a sex event. Positive affect was lower in the 24 h before this pericoital period, compared to other times. Negative affect did not significantly differ between before the pericoital period and other times. The findings suggest that depressed youth may have sex to regulate their positive affect and have implications for provision of their mental and physical health care.