Ixazomib plus daratumumab and dexamethasone: Final analysis of a phase 2 study among patients with relapsed/refractory multiple myeloma.

Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.

Racial differences in psychological stress and insulin sensitivity in non-Hispanic Black and White adolescents with overweight/obesity.

INTRODUCTION: Racial differences in type 2 diabetes risk persist among non-Hispanic Black and non-Hispanic White adolescents with overweight/obesity; however, the role of psychological stress in this disparity is less clear. PURPOSE: To examine racial differences in the association between psychological stress, insulin sensitivity (Si), acute insulin response to glucose (AIRg), and disposition index (DI) among non-Hispanic Black and non-Hispanic White adolescents with overweight/obesity. METHODS: Ninety-six adolescents (60% female; 51% non-Hispanic Black; 16.6 ± 1.8 years of age) with overweight/obesity (BMI percentile ≥ 85th percentile) were included in this analysis. Psychological stress was assessed using the 14-item Perceived Stress Scale. Glucose and insulin data from an intravenous glucose tolerance test was modeled to obtain Si, AIRg, and DI. Multivariable linear regression models were used to examine the association between race, psychological stress and metabolic outcomes (Si, AIRg, and DI). RESULTS: Race was a significant predictor of log-AIRg and log-DI (ps < 0.05) independent of all covariates in the main effect models. Lower Si (pinteraction = 0.014) and DI (pinteraction = 0.012) was also observed among Black adolescents who reported higher stress levels, whereas higher Si and DI was observed among non-Hispanic White adolescents reporting higher stress in the race interaction models. Race however, did not moderate the association between psychological stress and AIRg (p > 0.05), nor was stress associated with Si, AIRg, or DI ("p" "s" > 0.05) across all other models. CONCLUSIONS: Psychological stress may play an important and distinct role in shaping racial differences in type 2 diabetes risk among adolescents with overweight/obesity. Additional research is needed to understand the long-term effects of psychological stress on metabolic health among non-Hispanic Black and non-Hispanic White adolescents with overweight/obesity.

Provider Perspectives on Screening for Social Determinants of Health in Pediatric Settings: A Qualitative Study.

INTRODUCTION: Pediatric settings often screen children and/or caregivers for social determinants of health (SDH) needs. Although SDH awareness rose with COVID, questions remain regarding best practices for SDH screening in pediatric settings. METHOD: We assessed pediatric providers' perspectives on integrating SDH screening into patient care. Semistructured interviews were conducted with providers (n = 13) from 10 clinics. Interviews were transcribed, and themes were analyzed using the constant comparative method. RESULTS: Themes highlighted providers' awareness of structural limitations to address social needs identified by screening; implementation concerns; the unique role of pediatric providers for child health and well-being; provider comfort with assessing patients' social needs; patient considerations; the importance of relational health between pediatric providers and families, and between providers and community supports for effective screening; and unintended consequences. DISCUSSION: Pediatric providers endorse the need for SDH screening, but barriers in pediatric settings may hamper the process and reduce efficacy.

When Families Do Not Request Help: Assessing a Social Determinants of Health Screening Tool in Practice.

INTRODUCTION: Using pediatric social determinants of health screening data from a large medical system, we explored social needs dislosures and identified which needs were associated with resource connection requests. METHOD: Data came from records of outpatient pediatric patients (0-18 years) seen between October 2018 and March 2020 (39,251 encounters). We assessed percent of encounters where families (1) indicated a social need, and (2) requested a resource connection. We conducted multivariable logistic regression to identify which needs were associated with resource connection requests. RESULTS: Among all encounters, 8% indicated a need and 2% requested a resource connection. Among families indicating a need, needs associated with resource requests included: housing (odds ratio [OR], 3.49 [2.42-5.03]), employment (OR, 3.15 [2.21-4.50]), food (OR, 1.89 [1.41-2.52]), and transportation (OR, 1.82 [1.30-2.56]). DISCUSSION: Families seldom requested resource connections to address social needs. Better understanding families' interests in receiving assistance is an important next step in pediatric social determinants of health screening system development.

Inhaled Cannabis Suppresses Chemotherapy-Induced Neuropathic Nociception by Decoupling the Raphe Nucleus: A Functional Imaging Study in Rats.

BACKGROUND: Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei. METHODS: We assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ9-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level-dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas. RESULTS: Prior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ9-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization. CONCLUSIONS: Inhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ9-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.

Caregiver Influences on Eating Behaviors in Young Children: A Scientific Statement From the American Heart Association.

A substantial body of research suggests that efforts to prevent pediatric obesity may benefit from targeting not just what a child eats, but how they eat. Specifically, child obesity prevention should include a component that addresses reasons why children have differing abilities to start and stop eating in response to internal cues of hunger and satiety, a construct known as eating self-regulation. This review summarizes current knowledge regarding how caregivers can be an important influence on children's eating self-regulation during early childhood. First, we discuss the evidence supporting an association between caregiver feeding and child eating self-regulation. Second, we discuss what implications the current evidence has for actions caregivers may be able to take to support children's eating self-regulation. Finally, we consider the broader social, economic, and cultural context around the feeding environment relationship and how this intersects with the implementation of any actions. As far as we are aware, this is the first American Heart Association (AHA) scientific statement to focus on a psychobehavioral approach to reducing obesity risk in young children. It is anticipated that the timely information provided in this review can be used not only by caregivers within the immediate and extended family but also by a broad range of community-based care providers.

Parental substance use and child reward-driven eating behaviors.

Family history of substance use is a well-established risk factor for greater substance use in adolescence and adulthood. The biological vulnerability hypothesis proposes that family history of substance use might also confer risk for obesogenic eating behavior because of similar rewarding characteristics between substances and certain foods (e.g., processed foods high in refined carbohydrates and fat). Indeed, preliminary research shows that family history of substance use is linked with sweet liking and obesity in adults; however, it is unknown whether this factor is linked to eating behavior earlier in development. The present study (n = 52) tested the association of severity of parental nicotine dependence and alcohol use (drinking frequency, drinking quantity, binge drinking, and number of annual drinks consumed) with two types of child [Mage = 10.18 (0.83) years] eating behavior: homeostatic eatingbehavior, or eating regulated by internal satiety cues, and reward-driven eatingbehavior, or eating motivated by pleasure. Results indicated that-over and above the influence of child age, child biological sex, and family income-more severe parental nicotine dependence and frequent and/or heavy, frequent parental alcohol use were associated with significantly greater child reward-driven eating behaviors as indexed by the Food Responsiveness and Enjoyment of Food subscales on the Child Eating Behavior Questionnaire. Parental substance use was not associated with child homeostatic eating behavior as indexed by the Satiety Responsiveness subscale. Family history of substance use may be an important transdiagnostic risk factor that identifies children at risk for obesogenic, reward-driven eating behaviors.

Maternal nicotine dependence is associated with longitudinal increases in child obesogenic eating behaviors.

BACKGROUND: Meta-analysis shows that parental cigarette smoking is associated with child obesity. OBJECTIVES: This study tested for associations between severity of maternal nicotine dependence and longitudinal changes in child eating behavior in archival data analysis. METHODS: Maternal nicotine dependence was assessed with the Fagerstrom Test for Nicotine Dependence. Child eating behavior was assessed with the Child Eating Behavior Questionnaire when children were ages 4, 6, 8, and 10. RESULTS: Over and above the influence of child age, child biological sex, and family income-to-needs ratio, more severe maternal nicotine dependence was associated with greater increases in child Food Responsiveness (γ = 0.07, SEγ  = 0.03, P = .014, 95% CI [0.01, 0.13]) and Emotional Overeating (γ = 0.06, SEγ  = 0.03, P = .024, 95% CI [0.01, 0.11]) across 6 years. CONCLUSIONS: Maternal nicotine dependence may be a transdiagnostic risk factor that identifies children at risk for reward-driven, obesogenic eating behavior.

Sleep duration and quality are associated with eating behavior in low-income toddlers.

OBJECTIVE: The present study examined whether different sleep health parameters (duration, timing, and quality) are associated with obesity-related eating behaviors including emotional overeating, food responsiveness, enjoyment of food, satiety responsiveness, and eating in the absence of hunger (EAH), during toddlerhood. DESIGN: Among 134 low-income 33-month-old children, parents reported on child sleep parameters, including sleep quality (Children's Sleep Wake Scale; CSWS) and usual bedtimes and wake times on weekdays and weekends (weeknight sleep duration, weekday-to-weekend bedtime delay). Child eating behaviors were assessed using both observed and parent-report measures. Child Emotional Overeating, Food Responsiveness, Enjoyment of Food, and Satiety Responsiveness were measured by parent report using the Child Eating Behavior Questionnaire-Toddler. Observed child EAH was evaluated by measuring kilocalories of palatable foods consumed following a meal. Multivariable linear regression was used to examine the associations between sleep parameters and eating behaviors. RESULTS: Poorer child sleep quality was associated with greater Emotional Overeating (standardized ß = -0.20 (SE 0.09), p < .05) and greater Food Responsiveness (ß = -0.18 (SE 0.09), p < .05). Shorter child nighttime sleep duration was associated with greater EAH kcal consumed (standardized ß = -0.22 (SE 0.09), p < .05). Child bedtime delay was not associated with any of the eating behaviors, and no child sleep variables were associated with either Enjoyment of Food or Satiety Responsiveness. CONCLUSIONS: Shorter nocturnal sleep duration and poorer sleep quality during toddlerhood were associated with some, but not all, of the obesity-related eating behaviors. Poor sleep health may promote childhood obesity risk through different eating behavior pathways. As children growing up in poverty may experience greater sleep decrements, sleep duration and sleep quality may be important targets for intervention among low-income families with young children.

Familial psychosocial risk classes and preschooler body mass index: The moderating effect of caregiver feeding style.

BACKGROUND: Early child weight gain predicts adolescent and adult obesity, underscoring the need to determine early risk factors affecting weight status and how risk factors might be mitigated. Socioeconomic status, food insecurity, caregiver depressive symptomology, single parenthood, and dysfunctional parenting each have been linked to early childhood weight status. However, the associations between these risk factors and children's weight status may be moderated by caregiver feeding styles (CFS). Examining modifiable factors buffering risk could provide key information to guide early obesity intervention efforts. METHODS: This analysis used baseline data from the Growing Healthy project that recruited caregivers/child dyads (N = 626) from Michigan Head Start programs. Caregivers were primarily non-Hispanic white (62%) and African American (30%). After using latent class analysis to identify classes of familial psychosocial risk, CFS was tested as a moderator of the association between familial psychosocial risk class and child body mass index (BMI) z-score. RESULTS: Latent class analysis identified three familial psychosocial risk classes: (1) poor, food insecure and depressed families; (2) poor, single parent families; and (3) low risk families. Interactive effects for uninvolved feeding styles and risk group indicated that children in poor, food insecure, and depressed families had higher BMI z-scores compared to children in the low risk group. Authoritative feeding styles in low risk and poor, food insecure, and depressed families showed lower child BMI z-scores relative to poor, single parent families with authoritative feeding styles. CONCLUSIONS: Uninvolved feeding styles intensified the risk and an authoritative feeding style muted the risk conferred by living in a poor, food-insecure, and depressed family. Interventions that promote responsive feeding practices could help decrease the associations of familial psychosocial risks with early child weight outcomes.

Targeting self-regulation to promote health behaviors in children.

Poor self-regulation (i.e., inability to harness cognitive, emotional, motivational resources to achieve goals) is hypothesized to contribute to unhealthy behaviors across the lifespan. Enhancing early self-regulation may increase positive health outcomes. Obesity is a major public health concern with early-emerging precursors related to self-regulation; it is therefore a good model for understanding self-regulation and health behavior. Preadolescence is a transition when children increase autonomy in health behaviors (e.g., eating, exercise habits), many of which involve self-regulation. This paper presents the scientific rationale for examining self-regulation mechanisms that are hypothesized to relate to health behaviors, specifically obesogenic eating, that have not been examined in children. We describe novel intervention protocols designed to enhance self-regulation skills, specifically executive functioning, emotion regulation, future-oriented thinking, and approach bias. Interventions are delivered via home visits. Assays of self-regulation and obesogenic eating behaviors using behavioral tasks and self-reports are implemented and evaluated to determine feasibility and psychometrics and to test intervention effects. Participants are low-income 9-12 year-old children who have been phenotyped for self-regulation, stress, eating behavior and adiposity through early childhood. Study goals are to examine intervention effects on self-regulation and whether change in self-regulation improves obesogenic eating.

Maternal concerns about children overeating among low-income children.

Addressing overeating is essential to obesity treatment and prevention. The objectives of this study were to investigate maternal concern for child overeating, to identify associated participant characteristics and to determine if concern for child overeating is associated with maternal feeding practices. Low-income mothers (N=289) of children (mean age 70.8months) participated in a semi-structured interview. Themes of maternal concern for child overeating were identified and a coding scheme was reliably applied. Maternal feeding practices were measured by questionnaire and videotaped eating interactions. Logistic regressions were used to test the associations of participant characteristics with the presence of each theme, and bivariate analyses were used to test the associations of the presence of each theme with feeding practices. Three themes were identified: 1) mothers worry that their child does overeat, 2) mothers acknowledge that their child may overeat but indicate that it is not problematic because they manage their child's eating behavior, and 3) mothers acknowledge that their child may overeat but indicate that it is not problematic because of characteristics inherent to the child. Child obesity predicted the themes; mothers of obese and overweight children are more likely to be concerned about overeating. Themes were associated with lower levels of observed pressure to eat. Only Theme 2 was associated with greater restrictive feeding practices. Interventions that provide parents' practical, healthy ways to prevent child overeating may be helpful.

Surgency and negative affectivity, but not effortful control, are uniquely associated with obesogenic eating behaviors among low-income preschoolers.

Despite increased attention to the role of temperament in children's obesogenic eating behaviors, there is a paucity of research examining whether different dimensions of temperament may be differentially associated with specific eating behaviors among preschool-age children. The purpose of the current study was to examine whether three temperament dimensions (surgency, negative affectivity, and effortful control) were uniquely associated with six obesogenic eating behaviors (caregiver-reported food responsiveness, enjoyment of food, emotional overeating, satiety responsiveness, and tantrums over food; and observed eating in the absence of hunger) among low-income preschool-age children, covarying home environment quality. Results showed that temperament dimensions were differentially associated with different eating behaviors. Specifically, preschoolers with higher surgency were more likely to overeat in response to external cues, have frequent desire to eat, derive pleasure from food, and eat in the absence of hunger. In contrast, preschoolers with higher negative affectivity were more likely to have tantrums over being denied food and less likely to eat in the absence of hunger. Effortful control was not uniquely associated with obesogenic eating behavior. Findings remained significant even when home chaos was accounted for, suggesting that child surgency and negative affectivity are important to consider, independent of home environment. Results are discussed with regard to theoretical implications for the study of childhood obesity and for applied prevention implications.

Diurnal cortisol pattern, eating behaviors and overweight in low-income preschool-aged children.

This study examined, among children, the associations among chaos in the home, diurnal cortisol patterns, eating behaviors and being overweight. Participants included 331 low-income children aged 3-4years. Mean salivary cortisol-intercept (representing morning peak, 60min since waking) and cortisol-slope (representing diurnal decline after peak) were calculated using mixed models from samples obtained across 3days. Parents reported chaos in the home by questionnaire and responded to the Children's Eating Behavior Questionnaire, generating subscales Food Responsiveness (FR), Emotional Overeating (EO), Enjoyment of Food (EF), and Satiety Responsiveness (SR). Body mass index was categorized as overweight vs. not. Path analysis evaluated associations among chaos, cortisol patterns, eating behaviors, and weight status. Children living in more chaotic homes had lower morning cortisol levels, consistent with "hypocortisolism" reported among individuals who have experienced significant allostatic load as a result of substantial early life chronic stress. Among girls, the hypocortisolism pattern predicted a higher likelihood of being overweight both directly and mediated through reduced Satiety Responsiveness; in boys, the association of the hypocortisolism pattern with being overweight was mediated entirely through Emotional Overeating. In summary, our results provide support for the conceptual model that psychosocial stress contributes to hypocortisolism, which contributes directly to a higher likelihood of being overweight in girls, and indirectly through reduced Satiety Responsiveness in girls and through increased Emotional Overeating in boys.

A prospective series of patients with chronic Achilles tendinopathy treated with autologous-conditioned plasma injections combined with exercise and therapeutic ultrasonography.

Chronic Achilles tendinopathy is a difficult problem to manage, because it can result in significant patient morbidity. We conducted a prospective case series involving 26 patients (2 bilateral cases) with painful and ultrasound-confirmed Achilles tendinopathy for a minimum duration of 6 months. Our objective was to assess whether this condition can be effectively treated with a treatment protocol combining an intratendinous autologous-conditioned plasma injection followed by a standardized rehabilitation protocol. The rehabilitation protocol consisted of full weightbearing in a pneumatic cast boot for 6 weeks, therapeutic ultrasound treatment, and an eccentric exercise program. Our results showed statistically significant improvements in terms of pain (p < .0001), other symptoms (p = .0003), activities of daily living (p = .0002), sports activities (p = .0001), and quality of life (p = .0002). We believe that the use of autologous-conditioned plasma can provide a potential treatment solution for chronic Achilles tendinopathy.

Lung cancer diagnosis from proteomic analysis of preinvasive lesions.

Early detection may help improve survival from lung cancer. In this study, our goal was to derive and validate a signature from the proteomic analysis of bronchial lesions that could predict the diagnosis of lung cancer. Using previously published studies of bronchial tissues, we selected a signature of nine matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) mass-to-charge ratio features to build a prediction model diagnostic of lung cancer. The model was based on MALDI MS signal intensity (MALDI score) from bronchial tissue specimens from our 2005 published cohort of 51 patients. The performance of the prediction model in identifying lung cancer was tested in an independent cohort of bronchial specimens from 60 patients. The probability of having lung cancer based on the proteomic analysis of the bronchial specimens was characterized by an area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88) in this validation cohort. Eight of the nine features were identified and validated by Western blotting and immunohistochemistry. These results show that proteomic analysis of endobronchial lesions may facilitate the diagnosis of lung cancer and the monitoring of high-risk individuals for lung cancer in surveillance and chemoprevention trials.

Advances in hematopoietic stem cell research through mouse genetics.

PURPOSE OF REVIEW: Successful bone marrow transplantation involves migration of hematopoietic stem cells through the blood, entering the extravascular hematopoietic cords, lodging in the proper niche, and expanding and differentiating to produce large numbers of mature cells -- all without depletion of the stem cell pool. An additional variable in these processes is the age of both the donor bone marrow and the recipient. Basic stem cell biology and transplant biology aim to uncover the molecular mechanisms controlling these processes. RECENT FINDINGS: Mouse genetics is a frequently used tool that allows dissection of individual pathways that influence properties of hematopoietic stem cells. Recently, the conception of a niche has been expanded to include evidence for a vascular and an endosteal niche. Additionally, hematopoietic stem cell interactions within the niche have been further defined, documenting the importance of cell cycle, cell adhesion, response to cytokine stimulation and age-dependent functional changes. A new model for hematopoietic stem cell aging was proposed that supports the hypothesis that stem cell aging is at least partially due to an accumulation of DNA damage leading to exhaustion. SUMMARY: This review focuses on the last year's progress using mouse genetics as a tool to study intrinsic mechanisms of hematopoietic stem cell biology.