A descriptive study of sleep patterns and knowledge among department of juvenile services staff.

Study Objectives: Little is known about sleep health among staff in the US juvenile justice system. Poor sleep health is associated with negative mental and physical health, which may impact daily interactions and treatment of detained youth. The current study explored sleep-wake patterns and sleep health knowledge of Department of Juvenile Services (DJS) staff in Maryland (MD). Methods: DJS Staff (N = 218) were invited to complete a survey that queried staff on their own sleep-wake patterns, job role and schedule, and knowledge of youth sleep needs. Descriptive analyses and multivariate analyses of variance (MANCOVA) were conducted to summarize workers' sleep-wake patterns and examine differences by staff position and schedule. Results: Fifty-one percent of staff served as RAs who directly supervise the youth. Just over half (55%) worked in detention and 45% in treatment facilities. Staff reported sleeping 7.24 hours (SD = 4.10) on workdays and 8.59 hours (SD = 2.69) on non-workdays. RA staff working night/rotating versus day shifts reported the most sleep irregularity with larger weekend oversleep times. A little more than half of the staff (53.9%) were knowledgeable regarding youth sleep health with differences by position type. Conclusions: Findings show that DJS staff are meeting recommended sleep duration guidelines but are still experiencing sleep schedule and time in bed irregularity. Knowledge variability of youth sleep health across staff may necessitate focused educational programming. Overall, this study may inform future development and prioritization of sleep and circadian health interventions and educational campaigns for staff who work with detained juveniles. This paper is part of the Sleep and Circadian Health in the Justice System Collection.

Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: A preliminary investigation.

Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.

Associations between fears related to safety during sleep and self-reported sleep in men and women living in a low-socioeconomic status setting.

South Africans living in low socioeconomic areas have self-reported unusually long sleep durations (approximately 9-10 h). One hypothesis is that these long durations may be a compensatory response to poor sleep quality as a result of stressful environments. This study aimed to investigate whether fear of not being safe during sleep is associated with markers of sleep quality or duration in men and women. South Africans (n = 411, 25-50 y, 57% women) of African-origin living in an urban township, characterised by high crime and poverty rates, participated in this study. Participants are part of a larger longitudinal cohort study: Modelling the Epidemiologic Transition Study (METS)-Microbiome. Customised questions were used to assess the presence or absence of fears related to feeling safe during sleep, and the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index were used to assess daytime sleepiness, sleep quality and insomnia symptom severity respectively. Adjusted logistic regression models indicated that participants who reported fears related to safety during sleep were more likely to report poor sleep quality (PSQI > 5) compared to participants not reporting such fears and that this relationship was stronger among men than women. This is one of the first studies outside American or European populations to suggest that poor quality sleep is associated with fear of personal safety in low-SES South African adults.

Severe atopic dermatitis, sleep disturbance, and low light exposure.

STUDY OBJECTIVES: Atopic dermatitis (AD) is a chronic inflammatory skin disorder in children. AD worsens at night, particularly in severe disease. Low light exposure contributes to inflammation, poor sleep, and misalignment between circadian (24-hour) rhythms (biological clocks) and social clocks (weekday vs. weekend sleep timing), but has not been evaluated in AD. Our objective was to perform a cross-sectional study to determine whether there is an association between AD severity, recorded light exposure (RLE), and sleep measures in participants with AD and healthy controls. METHODS: Secondary data analysis from two prospective observational studies of 74 participants ages 5-17 years old with severe AD compared to others (healthy controls and mild/moderate AD). Participants wore actigraphy watches for at least 1 weekday and one weekend. Rest/activity and RLE (lux) were obtained from the watches and were analyzed to estimate duration and quality of sleep/light exposure. RESULTS: Participants (n = 74) were on average 10.9 ±â€…3.6 years old, with 45% female, 17% no AD, 27% mild, 32% moderate, and 24% severe AD. On weekends, severe AD participants versus others fell asleep at a similar time (23:52 ±â€…1:08 vs. 23:40 ±â€…1:29 mean clock-time hours ±â€…SD; p = 0.23), had similar sleep-onset latency (8.2 ±â€…8.7 vs. 12.7 ±â€…16.9 minutes; p = 0.28), but woke later (09:12 ±â€…1:04 vs. 08:13 ±â€…1:14 minutes; p < 0.01) resulting in a later sleep-midpoint (04:32 ±â€…0:53 vs. 03:49 ±â€…1:08 minutes; p = 0.02). Severe AD participants had lower levels of daytime RLE than others (mean-over-all-days: 1948.4 ±â€…2130.0 vs. 10341.3 ±â€…13453.8 lux; p = 0.01) and throughout seasons, weekdays, or weekend, yet had similar nighttime RLE. CONCLUSION: Severe AD is characterized by low RLE and sleep disturbance. Low RLE could potentially induce circadian misalignment, contributing to inflammation and worse disease in severe AD. Low RLE can also reflect altered lifestyle and behavior due to atopic disease impacts. Prospective studies are needed to test causality and the potential of bright light as an adjuvant therapy for severe AD.

AGuIX nanoparticle-nanobody bioconjugates to target immune checkpoint receptors.

This article presents bioconjugates combining nanoparticles (AGuIX) with nanobodies (VHH) targeting Programmed Death-Ligand 1 (PD-L1, A12 VHH) and Cluster of Differentiation 47 (CD47, A4 VHH) for active tumor targeting. AGuIX nanoparticles offer theranostic capabilities and an efficient biodistribution/pharmacokinetic profile (BD/PK), while VHH's reduced size (15 kDa) allows efficient tumor penetration. Site-selective sortagging and click chemistry were compared for bioconjugation. While both methods yielded bioconjugates with similar functionality, click chemistry demonstrated higher yield and could be used for the conjugation of various VHH. The specific targeting of AGuIX@VHH has been demonstrated in both in vitro and ex vivo settings, paving the way for combined targeted immunotherapies, radiotherapy, and cancer imaging.

Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation.

Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of DICER1-related tumor predisposition and identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for DICER1 germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of DICER1 experts joined ClinGen to form the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP), to create DICER1- specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 DICER1 variants were selected for piloting, including 14 known Pathogenic/Likely Pathogenic (P/LP) variants, 12 known Benign/Likely Benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the DICER1-specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating DICER1 variants should consider adopting this classification framework to encourage consistency and improve objectivity.

Sleep and circadian health in juvenile justice systems: A descriptive analysis.

OBJECTIVE: Few studies have explored sleep health and environmental influences on sleep and circadian health within juvenile justice facilities. The current study aims to describe sleep and circadian health of adolescents living in detention and treatment facilities. METHODS: Youth (N = 62) were recruited from 11 Department of Juvenile Services facilities. They completed a novel Youth Sleep and Daytime Behavior Questionnaire, daily sleep diary for seven consecutive mornings, and a brief poststudy interview. Healthcare staff completed a Youth Health Background survey for each participating youth. Facilities' 24-hour schedules were also obtained. RESULTS: Descriptive analyses were performed to capture the youths' sleep-wake experience while residing in Department of Juvenile Services facilities. Youth are obtaining the recommended total sleep time (M=8.9 hours, SD=1.2 hours) of 8-10 hours per night. However, they are taking twice as long to fall asleep (M=47 minutes SD=59 minutes) compared to the recommended sleep onset latency of 10-20 minutes. Youths' perceptions reveal potential reasons for long sleep onset latencies, including early facility sleep-wake schedules (78%) and overhead lights (60%) remaining on throughout the night. Furthermore, 37% of youth received facility-ordered behavioral sleep assessments, 36% were taking exogenous melatonin, and the majority of youth were prescribed at least one psychotropic medication. CONCLUSIONS: Findings suggest sleep-wake schedules and light exposure may be associated with an increase in symptoms of insomnia and/or circadian dysregulation. Based on the findings, facility-wide interventions are needed to improve the youths' sleep health.

cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

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.

A developmental perspective on sleep consistency: Preschool age through emerging adulthood.

OBJECTIVE/BACKGROUND: 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. METHODS: 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. RESULTS AND CONCLUSIONS: 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.

Nuclease-independent functions of RAG1 direct distinct DNA damage responses in B cells.

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.

Extending weeknight sleep of delayed adolescents using weekend morning bright light and evening time management.

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 ±â€…0.8 h) compared to the Control (-0.1 ±â€…0.8 h) group. By week 2, the Intervention group fell asleep 1.5 ±â€…0.7 h earlier and sleep duration increased by 1.2 ±â€…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.

Seasonality of Children's Height and Weight and Their Contribution to Accelerated Summer Weight Gain.

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) (ß = -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 (ß =.02, SE = 0.005, p <0 .0001), mainly among children who remained healthy weight throughout elementary school (ß = 0.014, SE = 0.003, p < 0.0001) and those who transitioned to a healthier weight status (ß = 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 (ß = 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.

Evaluation of a Circadian Rhythm and Sleep-Focused Mobile Health Intervention for the Prevention of Accelerated Summer Weight Gain Among Elementary School-Age Children: Protocol for a Randomized Controlled Feasibility Study.

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.

Gut microbiota alterations in response to sleep length among African-origin adults.

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 (<7hrs), normal (7-<9hrs), and long (≥9hrs). Forty-seven percent of US participants were classified as short sleepers and 88% of SA participants as long sleepers. Gut microbial composition analysis (16S rRNA gene sequencing) revealed that bacterial alpha diversity negatively correlated with sleep length (p<0.05). Furthermore, sleep length significantly contributed to the inter-individual beta diversity dissimilarity in gut microbial composition (p<0.01). Participants with both short and long-sleep durations exhibited significantly higher abundances of several taxonomic features, compared to normal sleep duration participants. The predicted relative proportion of two genes involved in the butyrate synthesis via lysine pathway were enriched in short sleep duration participants. Finally, co-occurrence relationships revealed by network analysis showed unique interactions among the short, normal and long duration sleepers. These results suggest that sleep length in humans may alter gut microbiota by driving population shifts of the whole microbiota and also specific changes in Exact Sequence Variants abundance, which may have implications for chronic inflammation associated diseases. The current findings suggest a possible relationship between disrupted sleep patterns and the composition of the gut microbiota. Prospective investigations in larger and more prolonged sleep researches and causally experimental studies are needed to confirm these findings, investigate the underlying mechanism and determine whether improving microbial homeostasis may buffer against sleep-related health decline in humans.

Later sleep timing predicts accelerated summer weight gain among elementary school children: a prospective observational study.

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.

Type 2 immunity is maintained during cancer-associated adipose tissue wasting.

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.

cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes.

Loss of major histocompatibility complex (MHC) class I and interferon-γ (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 κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell-dependent immune responses, even in ß2-microglobulin (ß2M)-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 noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

Meal timing relative to DLMO: Associations with BMI and body fat.

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 body mass index (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 dual-energy X-ray absorptiometry 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 = 0.25, SEb = 0.06, P< .001, longer feeding duration, b = 0.84, SEb = 0.06, P< .001, greater carbohydrate intake, b = 9.08, SEb = 3.55, P= .01, and greater sugar intake, b = 4.73, SEb = 1.83, P= .01. Last meal-DLMO was not associated with BMI in the full sample; however, among those with later DLMO (after 10:30 PM) last meal-DLMO was related to higher BMI, b = 0.92, SEb = 0.36, 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.

Workshop report. Circadian rhythm sleep-wake disorders: gaps and opportunities.

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.

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.