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IntroductionCraniopharyngioma is a brain tumor arising in the region of the hypothalamic-pituitary axis. Children and adolescents with craniopharyngioma have high survival rates, but often experience significant morbidity, including high rates of sleep disorders. Vulnerabilities to circadian disruption are present in this population, but little is known about circadian health.MethodsWe present exploratory circadian findings from a prospective trial at a single center. Data presented here are from the baseline timepoint. Fifty-three patients between the ages of 7 and 20 years provided salivary melatonin samples, following surgical resection and prior to completion of proton therapy, when indicated. We estimated dim light melatonin onset (DLMO) and collected additional sleep data from actigraphy, overnight polysomnography, and the multiple sleep latency test.ResultsAlmost half of participants did not have a valid DLMO estimate during the sampling window, with most being above the threshold at the first sample timepoint. Those with greater disease severity variables (greater hypothalamic involvement and the presence of diabetes insipidus) were significantly more likely to have missed DLMO. For those with valid estimates, DLMO timing correlated with BMI and other sleep variables, including mean sleep latency values on the MSLT.DiscussionThese findings suggest that a subset of those with pediatric craniopharyngioma may experience a phase advance and that this may relate to poorer prognostic indicators. Furthermore, circadian timing correlates with other sleep and health factors. Further research with earlier sampling is needed to better understand circadian rhythms in pediatric craniopharyngioma and associations with other health and disease variables.

Beyond sleep duration, the regularity of sleep patterns (e.g., sleep consistency), including variability in sleep timing (e.g., bedtime, wake time) and duration, is a critical marker of sleep health. Sleep consistency is captured using a variety of methods within the literature (e.g., sleep intraindividual variability, social jetlag), but most of the research focuses on adolescents.Drawing on a developmental perspective, this narrative review highlights how normative changes at the individual (e.g., biological, cognitive, and social) and contextual (e.g., home, school, sociocultural) levels may contribute to inconsistent sleep patterns across development.This review emphasizes how inconsistent sleep may increase across pivotal transitions throughout development (e.g., elimination of naps, puberty, summertime, entering college). Finally, recommendations for measuring sleep consistency and areas to address in future research are discussed.

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell–dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

Developing B cells generate DNA double-stranded breaks (DSBs) to assemble immunoglobulin receptor (Ig) genes necessary for the expression of a mature B cell receptor. These physiologic DSBs are made by the RAG endonuclease, which is comprised of the RAG1 and RAG2 proteins. In pre-B cells, RAG-mediated DSBs activate the ATM kinase to coordinate canonical and non-canonical DNA damage responses (DDR) that trigger DSB repair and B cell developmental signals, respectively. Whether this broad cellular response is distinctive to RAG DSBs is poorly understood. To delineate the factors that direct DDR signaling in B cells, we express a tetracycline-inducible Cas9 nuclease in Rag1-deficient pre-B cells. Both RAG- and Cas9-mediated DSBs at Ig genes activate canonical DDR. In contrast, RAG DSBs, but not Cas9 DSBs, induce the non-canonical DDR-dependent developmental program. This unique response to RAG DSBs is, in part, regulated by non-core regions of RAG1. Thus, B cells trigger distinct cellular responses to RAG DSBs through unique properties of the RAG endonuclease that promotes activation of B cell developmental programs.

Objectives and background Social demands of the school-year and summer environment may affect children’s sleep patterns and circadian rhythms during these periods. The current study examined differences in children’s sleep and circadian-related behaviors during the school-year and summer and explored the association between sleep and circadian parameters and change in body mass index (BMI) during these time periods. Methods This was a prospective observational study with 119 children ages 5 to 8 years with three sequential BMI assessments: early school-year (fall), late school-year (spring), and beginning of the following school-year in Houston, Texas, USA. Sleep midpoint, sleep duration, variability of sleep midpoint, physical activity, and light exposure were estimated using wrist-worn accelerometry during the school-year (fall) and summer. To examine the effect of sleep parameters, physical activity level, and light exposure on change in BMI, growth curve modeling was conducted controlling for age, race, sex, and chronotype. Results Children’s sleep midpoint shifted later by an average of 1.5 h during summer compared to the school-year. After controlling for covariates, later sleep midpoints predicted larger increases in BMI during summer, (γ = .0004, p = .03), but not during the school-year. Sleep duration, sleep midpoint variability, physical activity levels, and sedentary behavior were not associated with change in BMI during the school-year or summer. Females tended to increase their BMI at a faster rate during summer compared to males, γ = .06, p = .049. Greater amounts of outdoor light exposure (γ = −.01, p = .02) predicted smaller increases in school-year BMI. Conclusions Obesity prevention interventions may need to target different behaviors depending on whether children are in or out of school. Promotion of outdoor time during the school-year and earlier sleep times during the summer may be effective obesity prevention strategies during these respective times.

Study Objectives Shift sleep onset earlier and extend school-night sleep duration of adolescents. Methods Forty-six adolescents (14.5–17.9 years; 24 females) with habitual short sleep (≤7 h) and late bedtimes (≥23:00) on school nights slept as usual for 2 weeks (baseline). Then, there were three weekends and two sets of five weekdays in between. Circadian phase (Dim Light Melatonin Onset, DLMO) was measured in the laboratory on the first and third weekend. On weekdays, the “Intervention” group gradually advanced school-night bedtime (1 h earlier than baseline during week 1; 2 h earlier than baseline during week 2). Individualized evening time management plans (“Sleep RouTeen”) were developed to facilitate earlier bedtimes. On the second weekend, Intervention participants received bright light (~6000 lux; 2.5 h) on both mornings. A control group completed the first and third weekend but not the second. They slept as usual and had no evening time management plan. Weekday sleep onset time and duration were derived from actigraphy. Results Dim light melatonin onset (DLMO) advanced more in the Intervention (0.6 ± 0.8 h) compared to the Control (−0.1 ± 0.8 h) group. By week 2, the Intervention group fell asleep 1.5 ± 0.7 h earlier and sleep duration increased by 1.2 ± 0.7 h; sleep did not systematically change in the Control group. Conclusions This multi-pronged circadian-based intervention effectively increased school-night sleep duration for adolescents reporting chronic sleep restriction. Adolescents with early circadian phases may only need a time management plan, whereas those with later phases probably need both time management and morning bright light. Clinical Trials Teen School-Night Sleep Extension: An Intervention Targeting the Circadian System (#NCT04087603): https://clinicaltrials.gov/ct2/show/NCT04087603

BACKGROUND: Timing of eating relative to the dim light melatonin onset (DLMO) may serve as a modifiable risk factor for adverse cardiometabolic outcomes. The primary aim of this study was to examine whether the timing of eating relative to DLMO is associated with BMI, body fat, and diet in healthy adults without the confound of sleep deprivation. METHODS: Healthy men and women (N = 97), ages 18–50, with a habitual sleep duration of ≥ 6.5 hours and ≤ 8.5 hours completed 7 days of actigraphy and daily sleep and food diaries. Participants underwent a DXA scan and blood draws to assess DLMO in the clinical research unit. RESULTS: A shorter duration between DLMO and the average clock time of the last meal (last meal-DLMO) was related to a higher number of meals consumed, b = .25, SE(b) = .06, p < .001, longer feeding duration, b = .84, SE(b) = .06, p < .001, greater carbohydrate intake, b = 9.08, SE(b) = 3.55, p = .01, and greater sugar intake, b = 4.73, SE(b) = 1.83, p = .01. Last meal-DLMO was not associated with BMI in the full sample; however, among those with later DLMO (after 10:30pm) last meal-DLMO was related to higher BMI, b = .92, SE(b) =.36, p = .02. CONCLUSION: These results suggest that timing of last meal relative to DLMO may serve as a marker of circadian misalignment and that eating the last meal closer to DLMO may negatively impact dietary habits.

OBJECTIVES: To investigate associations between self-reported sleep duration and cardiometabolic (CM) risk factors in African-origin adults residing in five countries spanning the epidemiologic transition. DESIGN: Cross-sectional SETTING AND PARTICIPANTS: Ghanaian (n=491), South African (n=503), Jamaican (n=508), Seychellois (n=501) and American (n=480) men and women. MEASUREMENTS: Self-reported sleep duration was obtained using questionnaires. Sex and sitestratified logistic regression analyses investigated relationships between sleep duration, individual CM risk factors and a binary CM risk variable (presence of ≥3 CM risk factors), adjusting for age, physical activity and education. RESULTS: Sleep duration distributions varied by cohort: 44.5%, 41.4%, 35.9%, 16.8% and 2.5% of American, Jamaican, Seychellois, Ghanaian and South African men reported

Background The i♥rhythm project is a mobile health adaptation of interpersonal and social rhythm therapy designed to promote healthy sleep and behavioral rhythms among 5-8-year olds during summer for the prevention of accelerated summer weight gain. Objective This pilot study will examine the feasibility, acceptability, and preliminary efficacy of the i♥rhythm intervention. This will ensure that the research protocol and procedures work as desired and are acceptable to families in preparation for the fully powered randomized controlled trial. The proposed study will examine the willingness of participants to participate in the intervention and determine whether modifications to the intervention, procedures, and measures are needed before conducting a fully powered study. We will assess our ability to (1) recruit, consent, and retain participants; (2) deliver the intervention; (3) implement the study and assessment procedures; (4) assess the reliability of the proposed measures; and (5) assess the acceptability of the intervention and assessment protocol. Methods This study will employ a single-blinded 2-group randomized control design (treatment and no-treatment control) with randomization occurring after baseline (Time 0) and 3 additional evaluation periods (postintervention [Time 1], and 9 months [Time 2] and 12 months after intervention [Time 3]). A sample of 40 parent-child dyads will be recruited. Results This study was approved by the institutional review board of Baylor College of Medicine (H-47369). Recruitment began in March 2021. As of March 2022, data collection and recruitment are ongoing. Conclusions This study will address the role of sleep and circadian rhythms in the prevention of accelerated summer weight gain and assess the intervention’s effects on the long-term prevention of child obesity. Trial Registration ClinicalTrials.gov NCT04445740; https://clinicaltrials.gov/ct2/show/NCT04445740. International Registered Report Identifier (IRRID) DERR1-10.2196/37002

Background: While children have been shown to have increased BMI during the summer compared to the school year, it is not known if this may be due to seasonal variations in height or weight separately.Methods: Trained nurses measured heights (cm) and weights (kg) in a cohort of Kindergarteners (n = 7648) twice per year from the beginning of kindergarten through 5th grade. Variation in height and weight by season (school year vs. summer) was examined using separate mixed-effects models. Season, sex, and BMI trajectory group were tested as fixed effects. Random effects included repeated measurements of time, students nested within a school, intercept, and slope for growth over time. Similar models using BMIz as the outcome examined the interaction of height or weight with season.Results: The rate of height gain was greater during the school year (∼Sept to April) compared to summer (∼April to Sept) (β = -0.05, SE = 0.013, p < 0.0001). The rate of weight gain did not differ seasonally. Height gain was more strongly associated with increased BMIz during summer compared to the school year (β =.02, SE = 0.005, p p < 0.0001) and those who transitioned to a healthier weight status (β = 0.026, SE = 0.008, p = 0.004). We found a similar seasonal effect for the association between weight with BMIz among children who maintained a healthy weight status (β = 0.014, SE = 0.014, p < 0.0001).Conclusion: This study indicates seasonality in children’s height gain, gaining height at a faster rate during the school year compared to the summer, while weight gain remained relatively more consistent throughout the year. Seasonality in height and weight gain had the greatest impact on BMIz among children with a healthy weight status. Future research with more frequent measurements is needed to better understand the seasonal regulation of children’s growth and weight gain.

© 2019 Springer Nature limited. All rights reserved., We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγc heterodimer (IL-2Rβγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates., We thank B. Nordstrom, J. Nordstrom, P. Barrier and J. Barrier for the IPD Fund (Budget Number: 68-0341); CONACyT SNI (Mexico), CONACyT postdoctoral fellowship (Mexico) and IPD translational research program to D.-A.S.; NIH MSTP grant T32 GM007266 to S.Y.; JDRF (2-SRA-2016-236-Q-R) to U.Y.U.; la Caixa Fellowship (la Caixa Banking Foundation, Barcelona, Spain) to A.Q.-R.; FCT Portugal Ph.D. studentship to C.L.-A.; European Research Council (ERC StG, grant agreement 676832), FCT Investigator (IF/00624/2015), and the Royal Society (UF110046 and URF\R\180019) to G.J.L.B.; Marie Curie International Outgoing Fellowship (FP7-PEOPLE-2011-IOF 298976) to E.M.; Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship to C.D.W.; Washington Research Foundation to B.D.W.; NIH grant R35GM122543 to F.P.-A.; Mentored Clinical Scientist Development Award 1K08DK114563-01, and the American Gastroenterological Association Research Scholars Award to M.D.; NIH-RO1-AI51321, NIH-RO1-AI51321, Mathers Foundation, Younger Endowed Chair, and Howard Hughes Medical Institute to K.C.G.; and Howard Hughes Medical Institute and Michelson Medical Research Foundation to D.B.

Loss of major histocompatibility complex (MHC) class I and interferon (IFN)-γ sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor kappa B (NF-κB) signaling. Induction of non-canonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We show that induction of non-canonical NF-κB signaling induces T cell-dependent immune responses, even in beta-2-microglobulin (β2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of non-canonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade due to loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep–wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.

Summary Objectives: Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the development of other adipose tissue (AT) pathologies such as obesity have been well described, the immune microenvironment has not been studied in the context of cachexia. Methods: We performed bulk RNA-sequencing, cytokine arrays, and flow cytometry to characterize the immune landscape of visceral AT (VAT) in the setting of pancreatic and colorectal cancers. Results: The cachexia inducing factor IL-6 is strongly elevated in the wasting VAT of cancer bearing mice, but the regulatory type 2 immune landscape which characterizes healthy VAT is maintained. Pathologic skewing toward Th1 and Th17 inflammation is absent. Similarly, the VAT of patients with colorectal cancer is characterized by a Th2 signature with abundant IL-33 and eotaxin-2, albeit also with high levels of IL-6. Conclusions: Wasting AT during the development of cachexia may not undergo drastic changes in immune composition like those seen in obese AT. Our approach provides a framework for future immunologic analyses of cancer associated cachexia., Graphical Abstract Graphical Abstract

Sleep disorders are increasingly being characterized in modern society as contributing to a host of serious medical problems, including obesity and metabolic syndrome. Changes to the microbial community in the human gut have been reportedly associated with many of these cardiometabolic outcomes. In this study, we investigated the impact of sleep length on the gut microbiota in a large cohort of 655 participants of African descent, aged 25–45, from Ghana, South Africa (SA), Jamaica, and the United States (US). The sleep duration was self-reported via a questionnaire. Participants were classified into 3 sleep groups: short (

Many adolescents fall asleep too late to get enough sleep (8–10 h) on school nights. Morning bright light advances circadian rhythms and could help adolescents fall asleep earlier. Morning bright light treatment before school, however, is difficult to fit into their morning schedule; weekends are more feasible. We examined phase advances in response to morning light treatment delivered over one weekend. Thirty-seven adolescents (16 males; 14.7–18.0 years) who reported short school-night sleep (≤7 h) and late bedtimes (school-nights ≥23:00; weekend/non-school nights ≥24:00) slept as usual at home for ∼2 weeks (“baseline”) and then kept a fixed sleep schedule (baseline school-night bed and wake-up times ±30 min) for ∼1 week before living in the lab for one weekend. Sleep behavior was measured with wrist actigraphy and sleep diary. On Saturday morning, we woke each participant 1 h after his/her midpoint of baseline weekend/non-school night sleep and 1 h earlier on Sunday. They remained in dim room light (∼20 lux) or received 1.5 or 2.5 h of intermittent morning bright light (∼6000 lux) on both mornings. The dim light melatonin onset (DLMO), a phase marker of the circadian timing system, was measured on Friday and Sunday evenings to compute the weekend circadian phase shift. The dim room light and 1.5-h bright light groups advanced the same amount (0.6 ± 0.4 and 0.6 ± 0.5 h). The 2.5-h bright light group advanced 1.0 ± 0.4 h, which was significantly more than the other groups. These data suggest that it is possible to phase advance the circadian clock of adolescents who have late bedtimes and short school-night sleep in one weekend using light that begins shortly after their sleep midpoint.

Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior. Methods: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively. Results: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p

We examined phase shifts to bright morning light when sleep was restricted by delaying bedtimes. Adolescents (n = 6) had 10-h sleep/dark opportunities for 6 days. For the next 2 days, half were put to bed 4.5 h later and then allowed to sleep for 5.5 h (evening room light + sleep restriction). The others continued the 10-h sleep opportunities (sleep satiation). Then, sleep schedules were gradually shifted earlier and participants received bright light (90 min, ~6000 lux) after waking for 3 days. As expected, sleep satiation participants advanced (~2 h). Evening room light + sleep restriction participants did not shift or delayed by 2-4 h. Abbreviations: DLMO: dim light melatonin onset.

The maturation of sleep regulatory systems during adolescence in combination with psychosocial and societal pressures culminate in a “Perfect Storm” of short and ill-timed sleep and the associated consequences for many youngsters. This model, first described by Carskadon in 2011, guides our current thinking of adolescent sleep behavior. Since the original description, the field has moved forward with remarkable pace, and this review aims to summarize recent progress and describe how this new work informs our understanding of sleep regulation and sleep behavior during this developmental time frame.

Objective: We analyzed two cohorts of people with type 2 diabetes to evaluate the relationships between depression, sleep quality, and history of hypoglycemia. Research design and methods: Two adult cohorts from Chicago (n = 193) and Bangkok, Thailand (n = 282) with type 2 diabetes completed questionnaires to assess sleep quality, depressive symptoms, and hypoglycemia frequency. Proportional odds logistic regression models for each cohort adjusted for duration of therapy, insulin and sulfonylurea management, and other factors. Results: Those with hypoglycemia in both cohorts had a longer duration of diabetes, greater use of insulin, and worse sleep quality. The Chicago cohort used less sulfonylureas but had higher depressive symptom scores. The Thailand cohort had greater sulfonylurea use. In the final Thailand regression model, depressive symptoms were independently associated with hypoglycemia frequency. In both final Chicago and Thailand models, sleep quality was not associated with hypoglycemia frequency. Conclusions: In the Thailand cohort, depressive symptoms were associated with hypoglycemia frequency. Keywords: Diabetes mellitus, Type 2, Hypoglycemia, Depression, Sleep

Eveningness is associated with greater depressive symptoms in the general population. Depression and type 2 diabetes (T2D) commonly coexist. We aimed to explore the association between morningness-eveningness and depressive symptoms in T2D patients in the United States and in Thailand.T2D patients (n = 182) from an endocrinology clinic in Chicago, Illinois, and six hospitals in Thailand (n = 251) were enrolled.Diabetes history was collected. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale (CES-D). The Chicago cohort completed the Morningness-Eveningness Questionnaire (MEQ) and the Thai cohort completed the Composite Scale of Morningness (CSM). Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI).The mean (SD) CES-D score was 13.7 (9.1) in Chicago and 11.9 (6.4) in Thailand. In Chicago participants, after adjusting for age, sex, ethnicity, hemoglobin A1c, insulin use, and PSQI score, greater eveningness (lower MEQ scores) was associated with higher CESD scores (B = -0.117, p = 0.048). In Thai participants, after adjusting for age, sex, and PSQI score, eveningness (lower CSM score) was associated with higher CES-D score (B = -0.147, p = 0.016). In both cohorts, however, eveningness was not independently associated with the likelihood of being in the at-risk range for clinical depression (CES-D ≥ 16).Eveningness is independently associated with greater depressive symptoms in T2D in two different ethnic cohorts. The results support the association between individual differences in circadian rhythms and psychological functioning in T2D.

Introduction Older adolescents show heightened alertness in the evening close to the time of their Dim Light Melatonin Onset (DLMO), a time when the circadian system is most responsive to delaying light. We examined reported activities of adolescents around the time of their DLMO. Methods Forty-six adolescents (14.2-17.9 years; 24 females) who reported ≤7 h sleep on school nights and late bedtimes (school-night ≥ 23:00; non-school night ≥ midnight) slept at home on their usual school-year sleep schedule for 2 weeks. Participants reported their main activity via text message every hour from 16:00 until self-selected bedtime. After these 2 weeks, their DLMO was measured. We examined reported activities in the hour around the DLMO and the 2 hourly responses that followed on weeknights (Sunday-Thursday) to determine the most common activities (n=1380 responses). Logistic regression tested whether frequency of activities predicted whether a participant’s DLMO fell within the earliest (n=15; 19:31 ± 00:44), middle (n=16; 20:49 ± 00:20), or latest (n=15; 22:29±1:15) tertile. Results Overall, reported activities that consumed the most time were cell phone use (19.5%), homework (18.3%), and watching TV (15.1%). Adolescents who reported more homework, were more likely to have a DLMO in the middle tertile compared to the earliest and latest tertiles. Cell phone use was least likely in adolescents in the earliest DLMO tertile. TV watching did not predict DLMO group. Conclusion Adolescents who had the earliest DLMOs spent less time on their phones when light has the greatest delaying effect. These data may indicate that light from cell phone screens may delay circadian phase in this age group. Alternatively, cell phone use may be more likely if adolescents cannot fall asleep due to a later circadian cue for sleep onset. Support R01 HL112756 (Crowley)

Several studies since the 1990s have demonstrated that children increase their body mass index at a faster rate during summer months compared with the school year, leading some to conclude that the out-of-school summer environment is responsible. Other studies, however, have suggested that seasonality may play a role in children’s height and weight changes across the year. This article reviews evidence for seasonal differences in the rate of children’s height and weight gain and proposes potential physiological mechanisms that may explain these seasonal variations.

Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control the pupillary light reflex (PLR) and synchronize sleep-wake cycles, melatonin secretion, and metabolic processes to the 24-h day. PLR abnormalities in diabetic retinopathy (DR) suggest ipRGC dysfunction. We explored whether ipRGC dysfunction in DR is associated with impaired sleep, circadian rhythms and metabolic functioning. Methods: Healthy controls (n=6), type 2 diabetes (T2D) without DR (n=8), or T2D with at least moderate DR (n=11) participated. PLR inferred ipRGC function, HbA1c, and nocturnal urinary 6-sulfatoxymelatonin (aMT6s/creatinine ratio) were measured. Sleep was recorded by 7-day actigraphy. Dim light melatonin onset (DLMO) was assessed by sampling saliva in the 7 hours before self-reported bedtime. Results: Mean age was 54.6±5.4 yr. The relative PLR was significantly smaller in T2D-DR (control vs. T2D-noDR vs. T2D-DR: 0.32(0.10) vs. 0.26 (0.09) vs. 0.13 (0.11), p=0.003). Nocturnal aMT6s [8.3 (3.1) vs. 14.6 (14.3) vs. 1.9 (2.1) ng/mg, p=0.001] was significantly lower in T2D-DR. Sleep was more disturbed in T2D-DR than others as reflected by higher wake time after sleep onset (p=0.024), higher fragmentation index (p=0.007) and lower sleep efficiency (p=0.030). HbA1c was similar between T2D groups. T2D-DR were more likely to have no detectable rise of salivary melatonin in the evening (normal 16% vs. DM-noDR 14% vs. DM-DR 67%, p=0.049). Smaller PLRs correlated with lower aMT6s (r=0.652, p=0.001). Among T2D, lower aMT6s and smaller PLR associated with lower sleep efficiency (p=0.029-0.046) and more fragmented sleep (p=0.028-0.066). There was no relationship between PLR or aMT6s with HbA1c in T2D. PLR was smaller in those without vs. with DMLO [0.11 (0.09) vs. 0.29 (0.09), p Conclusion: T2D with DR had dysregulated melatonin rhythm and disrupted sleep, which significantly correlated with the degree of ipRGC dysfunction. Disclosure S. Reutrakul: None. J.C. Park: None. F. Chau: None. T. Baynard: None. M. Priyadarshini: None. S. Crowley: None. J. McAnany: None. Funding University of Illinois at Chicago

The purpose of this review is to synthesize the current evidence regarding biological changes to the regulation of sleep-wake behavior in adolescence, summarize the impact of environmental factors (e.g., media use, school start times) on sleep, and discuss the implication of these biological and behavioral changes for adolescent emotional, physical, and cognitive development. Although our basic understanding of the sleep regulatory process in adolescence has not shifted in recent years, emerging findings highlight the influence of environmental factors (e.g., media use) on sleep behavior. Furthermore, a flurry of recent experimental studies has bolstered our understanding of the influence of short sleep on cognitive and emotional functioning. Despite these advances, longitudinal data elucidating whether there are maturational changes in the impact to sleep loss on adolescent development are largely absent. A confluence of biological and environmental factors leads to short and ill-timed sleep among adolescents. Given the importance of sleep for the cognitive, emotional, and physical health in adolescence, the high prevalence of sleep loss in this population represents a public health issue.

Introduction Evening light can increase alertness and shift the circadian clock later (delay) and, in turn, delay sleep onset timing. We are examining whether reducing evening light exposure (by wearing sunglasses) paired with stable wake times can shift circadian and sleep onset times earlier in adolescents with Delayed Sleep-Wake Phase Disorder (DSWPD). Methods Fifteen adolescents (14.7–18.1 years; 4 male) diagnosed with DSWPD are included in this interim analysis. Participants sleep without restriction at home for a baseline week, and then complete a 2-week intervention. One group (Amber; n=7) wears glasses with amber lenses (Cocoons®, Live Eyewear) beginning 7 hours before their baseline mid-sleep time until self-selected bedtime or for 7 hours (corresponds to the phase delay region of the adolescent phase response curve to light). The amber lens transmits 14% of light to the eye and absorbs most short wavelength light. The frame blocks light from all angles. Amber participants are also instructed to wake at their average baseline school-morning wake-up time (±30 mins). Another group (Clear; n=8) wears identical glasses with clear lenses at the same time and wake time is unrestricted. Glasses wear time is monitored with an iButton placed at the temple tip. Dim Light Melatonin Onset (DLMO) is measured after the baseline week and after the 2-week intervention; 2 participants (one from each group) do not have melatonin data due to technical error. Sleep is measured with wrist actigraphy and sleep diaries throughout the study. DLMO and sleep onset changes (baseline-intervention) are compared between groups with t-tests. Results Amber DLMOs shifted 1.0±2.0h earlier (min-max: 0.4-h delay-5.0-h advance) and Clear DLMOs shifted 0.4±1.1h later (min-max: 2.0-h delay-0.6-h advance) [t(11)=1.60,p=0.14]. Average school-night sleep onset shifted earlier in both groups (Amber:0.4±1.3h; Clear:0.6±1.0h; t(13)=0.2,p=0.8]. Average non-school-night sleep onset shifted 1.1±1.0h earlier in Amber (min-max:0.6-h delay-2.2-h advance) and remained stable (0.03±1.0h) in Clear (min-max: 1.8-h delay-1.7-h advance) [t(13)=1.92,p=.08]. Conclusion Trends from this ongoing study suggest that amber-lensed glasses to block evening light plus stable wake-up times may shift circadian rhythms earlier. This strategy appears to help adolescents with DSWPD fall asleep earlier predominantly on non-school nights. Support (if any) AASMF Strategic Research Award (184-SR-17) to RRA

Introduction We are testing strategies to make fall asleep times earlier to extend sleep duration of sleep-deprived, delayed adolescents. We explored whether perceived sleep need was associated with the acceptability of an intervention which included earlier bedtimes on school nights and early morning bright light (BL) on one weekend. Methods Twenty-three participants (16.0±0.7 years; N=11 female) from the intervention group of a study of adolescents reporting ≤7 h sleep on school nights and late bedtimes (school-night≥23:00; non-school night≥midnight) were included. Participants estimated nightly sleep need during baseline. The intervention included shifting school-night bedtimes 1h earlier than each participant’s usual school night bedtime during the first week and 2h earlier than baseline during the second week. Evening time management goals were used to help participants get to bed earlier. Wake times remained stable because of early school start times. During the weekend in between these 2 weeks, participants lived in the laboratory and received very early morning BL on Saturday and Sunday from two light boxes (~6000 lux; three 50-minute exposures with 10-minute breaks). At the end of the study, an acceptability questionnaire asked about hypothetically engaging in different elements of the intervention (earlier bedtimes, morning BL) at home. Items were summed to create a composite acceptability score. Results Participants reported needing 7.8 h (SD=1.2; range=5-9.5h) of sleep. A linear regression demonstrated that needing more sleep was associated with less acceptability when controlling for age and sex, b=1.37, SEb=.60, p=.03. Conclusion Adolescents who felt they needed less sleep were more accepting of an intervention that required earlier bedtimes on school nights and waking up very early to receive BL on the weekend. Interventions that produce less weekend sleep deprivation, like including naps, might be more acceptable to all. Support R01HL105395 (S.J.C.)

Tissue‐resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T‐bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild‐type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin‐draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP‐NKT cells produce the majority of the IL‐4 in Peyer's patches and provide indirect help for B‐cell class switching to IgG1 in both transnuclear and wild‐type mice. Oral vaccination with α‐galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell‐sufficient mice. Transcriptional profiling reveals a unique signature of PP‐NKT cells, characterized by tissue residency. We thus define PP‐NKT as potentially important for surveillance for mucosal pathogens.

Significance Ipilimumab, an antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved “checkpoint”-blocking anticancer therapy. In mice, the response to antibodies against CTLA-4 depends entirely on expression of the Fcγ receptor. We developed H11, an alpaca heavy chain-only antibody fragment against CTLA-4 that lacks an Fc portion and inhibits interactions between CTLA-4 and its ligand. By using H11 to visualize CTLA-4 expression in the whole animal, we found that accessible CTLA-4 is largely confined to the tumor; however, H11 treatment has minimal effects on antitumor responses. Installing the murine IgG2a constant region on H11 greatly enhances antitumor response. We were thus able to dissociate CTLA-4 blockade from CTLA-4–dependent receptor engagement as an explanation for the antitumor effect., Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved “checkpoint”-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fcγ receptor (FcγR), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4–binding antibodies require an Fc domain for antitumor effect.

Context: Late adolescence is marked by a delay in sleep timing, which is partly driven by a delay shift of the circadian timing system. This study examined whether the sensitivity of the circadian system to light - the primary entraining stimulus to the circadian system - differs between pre- to mid-pubertal and late- to post-pubertal adolescents. Objective: To determine the influence of puberty on the sensitivity of the circadian system to light in humans Methods: Melatonin suppression to low and moderate light levels was assessed in 38pre- to mid-pubertal (9.1-14.7 years) and 29 late- to post-pubertal (11.5-15.9 years)adolescents. They received 1 hour of 4 light levels on consecutive nights: ~0.1 (near darkbaseline condition), 15, 150, and 500 lux. One group received evening light beginning at 2300 (n=39); a second group received morning light beginning at 0300(n=28). Salivary melatonin was sampled every 30 minutes. Melatonin suppression for15, 150 and 500 lux was calculated relative to unsuppressed baseline levels in the~0.1 lux setting, within individuals. Results: The pre- to mid-pubertal group showed significantly greater melatonin suppression to 15 lux (9.2 ± 20.5%), 150 lux (26.0 ± 17.7%), and 500 lux (36.9 ±11.4%) during evening light exposure compared to the late- to post-pubertal group (-5.3 ± 17.7%, 12.5 ± 17.3%, and 23.9 ± 21.7%, respectively; p < .05). No significant differences were seen between developmental groups in morning melatonin suppression. Conclusion: These results indicate support for a greater sensitivity to evening light in early pubertal children. The increased sensitivity to light in younger adolescents suggests that exposure to evening light could be particularly disruptive to sleep regulation for this group Refereed/Peer-reviewed

Objective Efficient treatments to phase-advance human circadian rhythms are needed to attenuate circadian misalignment and the associated negative health outcomes that accompany early-morning shift work, early school start times, jet lag, and delayed sleep phase disorder. This study compared three morning bright-light exposure patterns from a single light box (to mimic home treatment) in combination with afternoon melatonin. Methods Fifty adults (27 males) aged 25.9 ± 5.1 years participated. Sleep/dark was advanced 1 h/day for three treatment days. Participants took 0.5 mg of melatonin 5 h before the baseline bedtime on treatment day 1, and an hour earlier each treatment day. They were exposed to one of three bright-light (~5000 lux) patterns upon waking each morning: four 30-min exposures separated by 30 min of room light (2-h group), four 15-min exposures separated by 45 min of room light (1-h group), and one 30-min exposure (0.5-h group). Dim-light melatonin onsets (DLMOs) before and after treatment determined the phase advance. Results Compared to the 2-h group (phase shift = 2.4 ± 0.8 h), smaller phase-advance shifts were seen in the 1-h (1.7 ± 0.7 h) and 0.5-h (1.8 ± 0.8 h) groups. The 2-h pattern produced the largest phase advance; however, the single 30-min bright-light exposure was as effective as 1 h of bright light spread over 3.25 h, and it produced 75% of the phase shift observed with 2 h of bright light. Conclusions A 30-min morning bright-light exposure with afternoon melatonin is an efficient treatment to phase-advance human circadian rhythms.

Little is known about the light exposure in full-time office workers, who spend much of their workdays indoors. We examined the 24-hour light exposure patterns of 14 full-time office workers during a week in summer, and assessed their dim light melatonin onset (DLMO, a marker of circadian timing) at the end of the working week. Six workers repeated the study in winter. Season had little impact on the workers' schedules, as the timing of sleep, commute, and work did not vary by more than 30 minutes in the summer and winter. In both seasons, workers received significantly more morning light on workdays than weekends, due to earlier wake times and the morning commute. Evening light in the two hours before bedtime was consistently dim. The timing of the DLMO did not vary between season, and by the end of the working week, the workers slept at a normal circadian phase.

Older adolescents are particularly vulnerable to circadian misalignment and sleep restriction, primarily due to early school start times. Light can shift the circadian system and could help attenuate circadian misalignment; however, a phase response curve (PRC) to determine the optimal time for receiving light and avoiding light is not available for adolescents. We constructed light PRCs for late pubertal to postpubertal adolescents aged 14 to 17 years. Participants completed 2 counterbalanced 5-day laboratory sessions after 8 or 9 days of scheduled sleep at home. Each session included phase assessments to measure the dim light melatonin onset (DLMO) before and after 3 days of free-running through an ultradian light-dark (wake-sleep) cycle (2 h dim [~20 lux] light, 2 h dark). In one session, intermittent bright white light (~5000 lux; four 20-min exposures) was alternated with 10 min of dim room light once per day for 3 consecutive days. The time of light varied among participants to cover the 24-h day. For each individual, the phase shift to bright light was corrected for the free-run derived from the other laboratory session with no bright light. One PRC showed phase shifts in response to light start time relative to the DLMO and another relative to home sleep. Phase delay shifts occurred around the hours corresponding to home bedtime. Phase advances occurred during the hours surrounding wake time and later in the afternoon. The transition from delays to advances occurred at the midpoint of home sleep. The adolescent PRCs presented here provide a valuable tool to time bright light in adolescents.

Night eating is a complex behavior associated with disruptions in eating, sleep, and mood regulation. While night eating has been associated with alterations in neuroendocrine functioning, night eating and Night Eating Syndrome (NES) are not well understood in patients with prevalent metabolic conditions, such as diabetes. In this study, 194 adults with Type 2 diabetes completed questionnaires assessing night eating symptoms as well as eating, sleep, and depressive symptoms. Glycemic control data, as measured by hemoglobin A1c (HbA1c), were gathered from patient medical charts. Results indicated that 7% of participants met criteria for NES. Increased symptoms of night eating were associated with poorer glycemic control and disruptions in eating, sleep, and mood, including significantly increased likelihood of having HbA1c levels >7% and endorsing clinical levels of depressive symptoms. Increasing understanding of the relationship between night eating and metabolic and psychosocial functioning in patients with diabetes may provide new avenues for treatment of these patients.