The role of psychiatric symptoms, sociodemographic factors, and baseline sleep variables on pediatric insomnia treatment outcomes in a clinically referred population.

STUDY OBJECTIVES: The current study aimed to examine clinically relevant psychiatric and sociodemographic predictors of insomnia treatment outcomes in pediatric patients clinically referred for insomnia. METHODS: Pediatric patients (N = 1428; ages 1.5 - 18 years), presenting for insomnia evaluation in a medical/sleep center-based behavioral sleep clinic were followed for treatment as clinically indicated. According to patient age, parent/patients completed validated measures of insomnia severity, psychiatric symptoms, and sociodemographic measures. Patients were also categorized by treatment outcome status (i.e., not recommended to follow-up after initial evaluation and treatment session, successful treatment completion, lost to follow-up after initial evaluation and treatment session, and early termination) according to the clinically indicated treatment recommended and dose of treatment received. RESULTS: Youth had elevated scores on psychiatric screening indexes with affective problems being highest for all age groups. Other co-morbid sleep disorders were present in nearly 25% of insomnia patients and use of sleep aids (melatonin; hypnotics) was commonplace. Baseline insomnia severity significantly predicted sleep treatment trajectories and post-treatment insomnia severity with large effects for all age groups. Other clinically relevant predictors of insomnia treatment outcomes included medication use and externalizing mental health concerns in younger patients and internalizing mental health concerns and chronological age in older patients. Lack of treatment follow-up and premature treatment termination was observed for patients with the worst insomnia symptoms at time of initial evaluation. CONCLUSIONS: Pediatric health providers delivering insomnia treatment should take a developmentally sensitive approach that is proactive with regards to managing treatment barriers that are likely influenced by severity of insomnia and co-morbid mental health concerns.

Sleep Characteristics of an International Sample of Adult Gamers.

Introduction About 65% of adult Americans report playing video games. Despite potential impacts to functioning, there is limited research on the relationship between video game use and sleep, specifically among adults. The present study expands upon the literature by describing demographic, video game, and sleep characteristics of an international adult sample of gamers. Methods The participants were 3,481 adults aged 18 to 74 who responded to an online questionnaire about video game use (i.e., quantity of play, most common game type), general sleep characteristics (i.e., sleep onset latency [SOL]; duration, sleep timing, and sleep quality), and gaming-specific sleep disruptors (i.e., game-related night awakenings and sleep delays). Most identified as cisgender male (79.8%) and white (77%). Results Participants reported an average SOL of 24.63 minutes, and most (64.5%) had a sleep duration from 7 to 9 hours with an overall average of 8.42 hours. Most (58.7%) reported that their sleep quality was fair to very poor . Bed and wake times were generally delayed, with 51% reporting a late evening or early morning bedtime and an average wake time of 8:28 am. A majority (81.2%) indicated that their bedtime was delayed due to game-related activities, but game-related night awakenings were less common. Conclusion Although many report a sufficient amount of sleep, adult gamers tend to report sleep disruptions in other domains, particularly regarding a delayed sleep schedule and poor sleep quality. This may be attributable to game-related bedtime delays or other game-specific factors (e.g., game type) that should be evaluated in the future.

Effects of Modifiable Activity-Related Health Behaviors on the Sleep-Pain Relationship in Adolescents.

Poor sleep and chronic pain are commonly related in adolescents. Only 5% of adolescents meet recommendations for physical activity and screen time, both of which impact the experience of sleep and pain disturbances. Research is needed to better understand the sleep-pain relationship in adolescents and to identify potential protective factors, such as activity-related health behaviors. This study examined sleep, behaviors that influence activity (i.e., physical activity, screen time), and their interaction as predictors of pain in a sleep-disordered sample of 105 adolescents aged 12-18 presenting for polysomnography. A hierarchical multiple linear regression was conducted to examine these relationships. Consistent with hypotheses, worse insomnia predicted worse pain. However, other activity-related health behaviors did not influence this relationship, ps > .05. Findings suggest that sleep should be the focus of treatment for adolescents with primary sleep disorders to prevent the onset or exacerbation of pain.

Associations Among Sleep, Emotional Eating, and Body Dissatisfaction in Adolescents.

The literature on adolescent sleep has shown a bidirectional relationship between sleep difficulties and altered eating habits, including emotional eating. However, it is unclear if this relationship is related to preexisting body concerns, or if poor sleep is the prime contributor to emotional eating patterns. This study therefore seeks to examine body dissatisfaction as a moderator of the sleep-emotional eating relationship in an at-risk sample. Adolescents (N = 106) presenting for overnight polysomnography self-reported on time-in-bed, insomnia, body dissatisfaction, and emotional eating. Less time-in-bed was correlated with a greater desire for thinness and greater insomnia severity was related to overall emotional eating and eating in response to anxiety, anger, and frustration and in response to depression. Moderation analyses revealed that the relationships between time-in-bed and eating in response to feeling unsettled (b = -.002, 95% CI[- .003, - .001], p < .005) and eating in response to anxiety, anger, and frustration (b = -.01, 95% CI[- .01, - .001], p < .05) were exacerbated by worse body dissatisfaction. Optimizing sleep may attenuate the risk for disordered eating, particularly for adolescents with high body dissatisfaction.

Acute and chronic alcohol modulation of extended amygdala calcium dynamics.

The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.

Pharmacogenetic testing and monitoring of complete blood counts among Veterans newly prescribed thiopurine treatments: a retrospective cohort study.

Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA's efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021. Aggregate monthly counts of thiopurine prescriptions and associated lab tests were tabulated, and the trend in the proportion of patients tested was analyzed using the Mann-Kendall test. The proportion of patients undergoing PGx testing rose from 30.0% in 2010 to 47.5% in late 2014 (July-December). However, PGx testing and overall testing only increased slightly after the sentinel event, and orders levelled off over time at slightly lower levels than before the sentinel event. Very little change was seen in the overall proportion of individuals receiving any testing across all patients with new prescriptions from the time of the sentinel event in 2014 to the end of 2021. A large portion of patients prescribed thiopurine drugs did not receive testing that could help prevent the development of potential adverse events, leading to a predominantly reactive approach. Increased PGx testing may result in a more proactive approach to the prevention of adverse events due to genetic interaction.

The Influence of Arsenic Co-Exposure in a Model of Alcohol-Induced Neurodegeneration in C57BL/6J Mice.

Both excessive alcohol consumption and exposure to high levels of arsenic can lead to neurodegeneration, especially in the hippocampus. Co-exposure to arsenic and alcohol can occur because an individual with an Alcohol Use Disorder (AUD) is exposed to arsenic in their drinking water or food or because of arsenic found directly in alcoholic beverages. This study aims to determine if co-exposure to alcohol and arsenic leads to worse outcomes in neurodegeneration and associated mechanisms that could lead to cell death. To study this, mice were exposed to a 10-day gavage model of alcohol-induced neurodegeneration with varying doses of arsenic (0, 0.005, 2.5, or 10 mg/kg). The following were examined after the last dose of ethanol: (1) microglia activation assessed via immunohistochemical detection of Iba-1, (2) reactive oxygen and nitrogen species (ROS/RNS) using a colorimetric assay, (3) neurodegeneration using Fluoro-Jade® C staining (FJC), and 4) arsenic absorption using ICP-MS. After exposure, there was an additive effect of the highest dose of arsenic (10 mg/kg) in the dentate gyrus of alcohol-induced FJC+ cells. This additional cell loss may have been due to the observed increase in microglial reactivity or increased arsenic absorption following co-exposure to ethanol and arsenic. The data also showed that arsenic caused an increase in CYP2E1 expression and ROS/RNS production in the hippocampus which could have independently contributed to increased neurodegeneration. Altogether, these findings suggest a potential cyclical impact of co-exposure to arsenic and ethanol as ethanol increases arsenic absorption but arsenic also enhances alcohol's deleterious effects in the CNS.

Acute and chronic alcohol modulation of extended amygdala calcium dynamics.

The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are reciprocally connected nodes of the extended amygdala thought to play an important role in alcohol consumption. Studies of immediate-early genes indicate that BNST and CeA are acutely activated following alcohol drinking and may signal alcohol reward in nondependent drinkers, while increased stress signaling in the extended amygdala following chronic alcohol exposure drives increased drinking via negative reinforcement. However, the temporal dynamics of neuronal activation in these regions during drinking behavior are poorly understood. In this study, we used fiber photometry and the genetically encoded calcium sensor GCaMP6s to assess acute changes in neuronal activity during alcohol consumption in BNST and CeA before and after a chronic drinking paradigm. Activity was examined in the pan-neuronal population and separately in dynorphinergic neurons. BNST and CeA showed increased pan-neuronal activity during acute consumption of alcohol and other fluid tastants of positive and negative valence, as well as highly palatable chow. Responses were greatest during initial consummatory bouts and decreased in amplitude with repeated consumption of the same tastant, suggesting modulation by stimulus novelty. Dynorphin neurons showed similar consumption-associated calcium increases in both regions. Following three weeks of continuous alcohol access (CA), calcium increases in dynorphin neurons during drinking were maintained, but pan-neuronal activity and BNST-CeA coherence were altered in a sex-specific manner. These results indicate that BNST and CeA, and dynorphin neurons specifically, are engaged during drinking behavior, and activity dynamics are influenced by stimulus novelty and chronic alcohol.

Exploring Bidirectional Relationships: Child Sleep Duration, Child Behavior Problems, and Parenting Stress in Families of Children with Autism Spectrum Disorder.

Background: Youth with Autism Spectrum Disorder (ASD) are at-risk for sleep and behavior problems, and their parents are at-risk for high stress. Child sleep duration, behavior problems, and parenting stress are interrelated; however, directionality of these associations is unclear and research including youth with ASD is lacking. Using a day-to-day, within-person design, this study explores the directionality of these relationships in families of children with ASD. Method: Twenty-six children (ages 3-5, 73.1% male, 65.4% Hispanic/Latino) with ASD and their mothers participated in a 14-day study. Child sleep duration (parent-report and actigraphy), behavior problems, and parenting stress were measured daily. Constructs were decomposed into their within- and between-person components and analyzed with random intercept cross-lagged panel models. Results: While between-person relationships were directionally expected in that shorter sleep, more behavior problems, and greater parenting stress were associated, within-person relationships were complicated. Better-than-average child behavior was associated with less next-day parenting stress, yet more parenting stress than average was associated with better next-day child behavior. As expected, longer-than-average child sleep was associated with less next-day parenting stress, while greater child behavior problems were associated with less sleep that night. Conclusions: Understanding the directionality of associations between child and parent factors allows for the optimization of interventions to improve the quality of life for families of children with ASD. Interventions that target child behavior and/or help parents manage stress while maintaining effective parenting strategies for sleep and behavior may be useful.

A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization's Role as a Treatment Modality.

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, ß cells also secrete small amounts of insulin every 4-8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, ß-cell mass is reduced due to apoptosis and ß cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

An inducible model of chronic hyperglycemia.

Transgene driven expression of Escherichia coli nitroreductase (NTR1.0) renders animal cells susceptible to the antibiotic metronidazole (MTZ). Many NTR1.0/MTZ ablation tools have been reported in zebrafish, which have significantly impacted regeneration studies. However, NTR1.0-based tools are not appropriate for modeling chronic cell loss as prolonged application of the required MTZ dose (10 mM) is deleterious to zebrafish health. We established that this dose corresponds to the median lethal dose (LD50) of MTZ in larval and adult zebrafish and that it induced intestinal pathology. NTR2.0 is a more active nitroreductase engineered from Vibrio vulnificus NfsB that requires substantially less MTZ to induce cell ablation. Here, we report on the generation of two new NTR2.0-based zebrafish lines in which acute ß-cell ablation can be achieved without MTZ-associated intestinal pathology. For the first time, we were able to sustain ß-cell loss and maintain elevated glucose levels (chronic hyperglycemia) in larvae and adults. Adult fish showed significant weight loss, consistent with the induction of a diabetic state, indicating that this paradigm will allow the modeling of diabetes and associated pathologies.

Association of Prostate-Specific Antigen Screening Rates With Subsequent Metastatic Prostate Cancer Incidence at US Veterans Health Administration Facilities.

Importance: There is controversy about the benefit of prostate-specific antigen (PSA) screening. Prostate-specific antigen screening rates have decreased since 2008 in the US, and the incidence of metastatic prostate cancer has increased. However, there is no direct epidemiologic evidence of a correlation between population PSA screening rates and subsequent metastatic prostate cancer rates. Objective: To assess whether facility-level variation in PSA screening rates is associated with subsequent facility-level metastatic prostate cancer incidence. Design, Setting, and Participants: This retrospective cohort used data for all men aged 40 years or older with an encounter at 128 facilities in the US Veterans Health Administration (VHA) from January 1, 2005, to December 31, 2019. Exposures: Yearly facility-level PSA screening rates, defined as the proportion of men aged 40 years or older with a PSA test in each year, and long-term nonscreening rates, defined as the proportion of men aged 40 years or older without a PSA test in the prior 3 years, from January 1, 2005, to December 31, 2014. Main Outcomes and Measures: The main outcomes were facility-level yearly counts of incident metastatic prostate cancer diagnoses and age-adjusted yearly metastatic prostate cancer incidence rates (per 100 000 men) 5 years after each PSA screening exposure year. Results: The cohort included 4 678 412 men in 2005 and 5 371 701 men in 2019. Prostate-specific antigen screening rates decreased from 47.2% in 2005 to 37.0% in 2019, and metastatic prostate cancer incidence increased from 5.2 per 100 000 men in 2005 to 7.9 per 100 000 men in 2019. Higher facility-level PSA screening rates were associated with lower metastatic prostate cancer incidence 5 years later (incidence rate ratio [IRR], 0.91 per 10% increase in PSA screening rate; 95% CI, 0.87-0.96; P < .001). Higher long-term nonscreening rates were associated with higher metastatic prostate cancer incidence 5 years later (IRR, 1.11 per 10% increase in long-term nonscreening rate; 95% CI, 1.03-1.19; P = .01). Conclusions and Relevance: From 2005 to 2019, PSA screening rates decreased in the national VHA system. Facilities with higher PSA screening rates had lower subsequent rates of metastatic prostate cancer. These data may be used to inform shared decision-making about the potential benefits of PSA screening among men who wish to reduce their risk of metastatic prostate cancer.

Insight Into the Adolescent Patient Experience With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease in youth, yet little is known about the adolescent patient's experience with NAFLD, which is key for treatment engagement. We examined adolescents' experiences with NAFLD diagnosis, thoughts on how NAFLD affects their daily life, understanding and perceptions of diagnosis and treatment, and impressions of how to improve care. METHODS: Utilizing a mixed-method design, adolescents with NAFLD (N = 16; Mean age = 15.8 years; Mean BMI = 37 kg/m 2 ) participated in focus groups. To supplement qualitative data, adolescents and their caregiver completed measures assessing illness perceptions, adolescent quality of life, and eating/activity behaviors. RESULTS: Focus group themes suggested reactions to diagnosis varied from unconcerned to anxious. NAFLD diagnosis occurred within the context of other psychological/medical concerns and was not perceived to affect most adolescents' daily lives. Although adolescents understood general contributors to NAFLD, comprehension of their diagnosis varied. Adolescents were more likely to make lifestyle changes when families were supportive, and they preferred tailored recommendations for health behavior change from the healthcare team. Notably, 62.5% of adolescents were more concerned about their weight than NAFLD. Almost half (43.8%) identified as food insecure. CONCLUSIONS: Adolescents with NAFLD may benefit from personalized treatment. Care could be enhanced by ensuring comprehension of diagnosis, problem-solving personal, and family barriers and increasing family support. Harnessing adolescents' desire for weight loss may be a more salient driver for change in disease status. Interventions should also address systemic barriers such as food insecurity to ensure equitable care.

Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology.

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

Racial and Ethnic Disparities in Prostate Cancer Outcomes in the Veterans Affairs Health Care System.

Importance: Prostate cancer (PCa) disproportionately affects African American men, but research evaluating the extent of racial and ethnic disparities across the PCa continuum in equal-access settings remains limited at the national level. The US Department of Veterans Affairs (VA) Veterans Hospital Administration health care system offers a setting of relatively equal access to care in which to assess racial and ethnic disparities in self-identified African American (or Black) veterans and White veterans. Objective: To determine the extent of racial and ethnic disparities in the incidence of PCa, clinical stage, and outcomes between African American patients and White patients who received a diagnosis or were treated at a VA hospital. Design, Setting, and Participants: This retrospective cohort study included 7 889 984 veterans undergoing routine care in VA hospitals nationwide from 2005 through 2019 (incidence cohort). The age-adjusted incidence of localized and de novo metastatic PCa was estimated. Treatment response was evaluated, and PCa-specific outcomes were compared between African American veterans and White veterans. Residual disparity in PCa outcome, defined as the leftover racial and ethnic disparity in the outcomes despite equal response to treatment, was estimated. Exposures: Self-identified African American (or Black) and White race and ethnicity. Main Outcomes and Measures: Time to distant metastasis following PCa diagnosis was the primary outcome. Descriptive analyses were used to compare baseline demographics and clinic characteristics. Multivariable logistic regression was used to evaluate race and ethnicity association with pretreatment clinical variables. Multivariable Cox regression was used to estimate the risk of metastasis. Results: Data from 7 889 984 veterans from the incidence cohort were used to estimate incidence, whereas data from 92 269 veterans with localized PCa were used to assess treatment response. Among 92 269 veterans, African American men (n = 28 802 [31%]) were younger (median [IQR], 63 [58-68] vs 65 [62-71] years) and had higher prostate-specific antigen levels (>20 ng/mL) at the time of diagnosis compared with White men (n = 63 467; [69%]). Consistent with US population-level data, African American veterans displayed a nearly 2-fold greater incidence of localized and de novo metastatic PCa compared with White men across VA centers nationwide. Among veterans screened for PCa, African American men had a 29% increased risk of PCa detection on a diagnostic prostate biopsy compared with White (hazard ratio, 1.29; 95% CI, 1.27-1.31; P < .001). African American men who received definitive primary treatment of PCa experienced a lower risk of metastasis (hazard ratio, 0.89; 95% CI, 0.83-0.95; P < .001). However, African American men who received nondefinitive treatment classified as "other" were more likely to develop metastasis (adjusted hazard ratio, 1.29; 95% CI, 1.17-1.42; P < .001). Using the actual rate of metastasis from veterans who received definitive primary treatment, a persistent residual metastatic burden for African American men was observed across all National Comprehensive Cancer Network risk groups (low risk, 4 vs 2 per 100 000; intermediate risk, 13 vs 6 per 100 000; high risk, 19 vs 9 per 100 000). Conclusions and Relevance: This cohort analysis found significant disparities in the incidence of localized and metastatic PCa between African American veterans and White veterans. This increased incidence is a major factor associated with the residual disparity in PCa metastasis observed in African American veterans compared with White veterans despite their nearly equal response to treatment.

Prevalence of somatic and pain complaints and associations with sleep disturbance in adolescents with insomnia presenting to a behavioral sleep medicine clinic.

STUDY OBJECTIVES: Sleep problems are highly comorbid with pediatric pain, yet there is a dearth of research on how pain and somatic complaints impact adolescent insomnia presentation and response to cognitive-behavioral therapy for insomnia (CBT-I). This study aims to (1) determine the prevalence of parent-reported somatic/pain complaints in adolescents with insomnia presenting to a behavioral sleep clinic, (2) assess the impact of somatic/pain complaints on initial sleep presentation, and (3) assess the impact of baseline somatic/pain complaints on response to CBT-I. METHODS: Participants included adolescents (n = 375) presenting to a behavioral sleep medicine center with a primary diagnosis of insomnia. As a part of clinical care, pre-evaluation measures were completed including the Pediatric Insomnia Severity Index, Adolescent Sleep Hygiene Scale, Adolescent Sleep Wake Scale, and Child Behavior Checklist. The Somatic Syndrome Scale of the Child Behavior Checklist measured somatic complaints and teens were categorized as endorsing pain if reported to experience aches/pains, headaches, or stomachaches. Adolescents completed the Pediatric Insomnia Severity Index at end of treatment. RESULTS: Most adolescents had parent-reported somatic (61.1%) and/or pain complaints: headaches (66.6%), stomachaches (48.5%), and aches/pains (45.1%). Greater somatic and pain complaints predicted a worse sleep presentation at intake (all P < .05). After controlling for insomnia severity at intake, neither end-of-treatment insomnia severity nor treatment status were predicted by somatic and pain complaints at intake. CONCLUSIONS: Results suggest that parent-reported somatic/pain complaints are prevalent in > 50% of adolescents seeking behavioral insomnia treatment. Although complaints are associated with more severe insomnia at intake, they do not appear to interfere with treatment response. CITATION: Van Dyk TR, Krietsch KN, King CD, Byars KC. Prevalence of somatic and pain complaints and associations with sleep disturbance in adolescents with insomnia presenting to a behavioral sleep medicine clinic. J Clin Sleep Med. 2022;18(1):151-160.

A Review of the Most Impactful Published Pharmacotherapy-Pertinent Literature of 2019 and 2020 for Clinicians Caring for Patients With Thermal or Inhalation Injury.

Keeping abreast with current literature can be challenging, especially for practitioners caring for patients sustaining thermal or inhalation injury. Practitioners caring for patients with thermal injuries publish in a wide variety of journals, which further increases the complexity for those with resource limitations. Pharmacotherapy research continues to be a minority focus in primary literature. This review is a renewal of previous years' work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Sixteen geographically dispersed, board-certified pharmacists participated in the review. A MeSH-based, filtered search returned 1536 manuscripts over the previous 2-year period. After manual review and exclusions, only 98 (6.4%) manuscripts were determined to have a potential impact on current pharmacotherapy practices and included in the review. A summary of the 10 articles that scored highest are included in the review. Nearly half of the reviewed manuscripts were assessed to lack a significant impact on current practice. Despite an increase in published literature over the previous 2-year review, the focus and quality remain unchanged. There remains a need for investment in well-designed, high impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries.

Chemogenetic manipulation of astrocytic signaling in the basolateral amygdala reduces binge-like alcohol consumption in male mice.

Binge drinking is a common occurrence in the United States, but a high concentration of alcohol in the blood has been shown to have reinforcing and reciprocal effects on the neuroimmune system in both dependent and non-dependent scenarios. The first part of this study examined alcohol's effects on the astrocytic response in the central amygdala and basolateral amygdala (BLA) in a non-dependent model. C57BL/6J mice were given access to either ethanol, water, or sucrose during a "drinking in the dark" paradigm, and astrocyte number and astrogliosis were measured using immunohistochemistry. Results indicate that non-dependent consumption increased glial fibrillary acidic protein (GFAP) density but not the number of GFAP+ cells, suggesting that non-dependent ethanol is sufficient to elicit astrocyte activation. The second part of this study examined how astrocytes impacted behaviors and the neurochemistry related to alcohol using the chemogenetic tool, DREADDs (designer receptors exclusively activated by designer drugs). Transgenic GFAP-hM3Dq mice were administered clozapine N-oxide both peripherally, affecting the entire central nervous system (CNS), or directly into the BLA. In both instances, GFAP-Gq-signaling activation significantly reduced ethanol consumption and correlating blood ethanol concentrations. However, GFAP-Gq-DREADD activation throughout the CNS had more broad effects resulting in decreased locomotor activity and sucrose consumption. More targeted GFAP-Gq-signaling activation in the BLA only impacted ethanol consumption. Finally, a glutamate assay revealed that after GFAP-Gq-signaling activation glutamate concentrations in the amygdala were partially normalized to control levels. Altogether, these studies support the theory that astrocytes represent a viable target for alcohol use disorder therapies.

SOX9 modulates cancer biomarker and cilia genes in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with high mortality. The cellular origins of PDAC are largely unknown; however, ductal cells, especially centroacinar cells (CACs), have several characteristics in common with PDAC, such as expression of SOX9 and components of the Notch-signaling pathway. Mutations in KRAS and alterations to Notch signaling are common in PDAC, and both these pathways regulate the transcription factor SOX9. To identify genes regulated by SOX9, we performed siRNA knockdown of SOX9 followed by RNA-seq in PANC-1s, a human PDAC cell line. We report 93 differentially expressed (DE) genes, with convergence on alterations to Notch-signaling pathways and ciliogenesis. These results point to SOX9 and Notch activity being in a positive feedback loop and SOX9 regulating cilia production in PDAC. We additionally performed ChIP-seq in PANC-1s to identify direct targets of SOX9 binding and integrated these results with our DE gene list. Nine of the top 10 downregulated genes have evidence of direct SOX9 binding at their promoter regions. One of these targets was the cancer stem cell marker EpCAM. Using whole-mount in situ hybridization to detect epcam transcript in zebrafish larvae, we demonstrated that epcam is a CAC marker and that Sox9 regulation of epcam expression is conserved in zebrafish. Additionally, we generated an epcam null mutant and observed pronounced defects in ciliogenesis during development. Our results provide a link between SOX9, EpCAM and ciliary repression that can be exploited in improving our understanding of the cellular origins and mechanisms of PDAC.

Repetitive mild traumatic brain injury causes synergistic effects on mortality.

Repetitive mild TBI (rmTBI) events are common in the U.S. However, rmTBI is challenging to study and this contributes to a poor understanding of mechanistic bases for disease following these injuries. We used fruit flies (D. melanogaster) and a modified version of the high-impact trauma (HIT) method of TBI to assess the pattern of mortality observed after rmTBI. We found that the pattern of mortality was synergistic after a critical number of injuries, similar to that observed previously at more moderate levels of TBI severity. The identity of cellular and molecular factors which contribute to the synergistic effect on mortality remain unknown, but this model offers a platform for investigation into such factors.