A Comparison of Family Management Between Families of Children With Autism Spectrum Disorder and Families of Children With Down Syndrome.

INTRODUCTION: This cross-sectional study aimed to (1) compare family management between families of children with autism spectrum disorder (ASD) or Down syndrome and (2) evaluate the contribution of the child (ASD behaviors, feeding difficulties, sleep disturbances), caregiver (mental health) and family (social support) factors to the caregiver's perceived condition management ability and effort. METHOD: Eighty-five caregivers (56 ASD, 29 Down syndrome) completed quantitative instruments online. Data analysis included independent samples t-tests and multiple linear regression. RESULTS: There were no significant differences in the dimensions of family management between groups. More ASD behaviors were associated with lower condition management ability and higher condition management effort. Lower perceived social support and higher caregiver age were associated with lower condition management ability. DISCUSSION: Integrating care into family life may be more challenging when the child has more social differences and behavioral rigidity. Nursing care should include an assessment of family social support.

A nondepleting anti-CD19 antibody impairs B cell function and inhibits autoimmune diseases.

B cells contribute to multiple aspects of autoimmune disorders, and B cell-targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti-human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell-dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell-targeting therapies in treatment of autoimmune conditions without causing B cell depletion.

Rapid and Simple Buffer Exchange Using Cation-Exchange Chromatography to Improve Point-of-Care Detection of Pharmacological Agents.

The current COVID-19 pandemic has highlighted the power, speed, and simplicity of point-of-care (POC) diagnostics. POC diagnostics are available for a wide range of targets, including both drugs of abuse as well as performance-enhancing drugs. For pharmacological monitoring, minimally invasive fluids such as urine and saliva are commonly sampled. However, false positives or negatives caused by interfering agents excreted in these matrices may confound results. For example, false positives have, in most cases, prevented the use of POC diagnostics for pharmacological agent detection; the consequence is that centralized labs are instead tasked to perform these screenings, resulting in significant delays between sampling and testing. Thus, a rapid, simple, and inexpensive methodology for sample purification is required for the POC to reach a field-deployable tool for the pharmacological human health and performance assessments. Buffer exchange is a simple, rapid approach to remove interfering agents, but has traditionally been difficult to perform on small pharmacological molecules. Therefore, in this communication, we use salbutamol, a performance-enhancing drug, as a case example to demonstrate the efficacy of ion-exchange chromatography as a technique to perform buffer exchange for charged pharmacological agents. This manuscript demonstrates the efficacy of this technique leveraging a commercial spin column to remove interfering agents found in simulant urines, such as proteins, creatinine, and urea, while retaining salbutamol. The utility and efficacy of the method was then confirmed in actual saliva samples. The eluent was then collected and run on the lateral flow assays (LFAs), improving the reported limit of detection by over 5× (new lower limit of detection of 10 ppb compared to reported 60 ppb by the manufacturer) while simultaneously removing noise due to background interfering agents.

Sterilization and reuse of masks for a standardized exhaled breath collection device by autoclaving.

Exhaled breath research has been hindered by a lack of standardization in collection and analysis methodologies. Recently, the Respiration Collector forIn VitroAnalysis (ReCIVA) sampling device has illustrated the potential to provide a consistent and convenient method for exhaled breath collection onto adsorbent media. However, the significant costs, compared to exhaled breath bags, associated with the standardized collector is believed to be the reason for limited widespread use by researchers in the exhaled breath field. For example, in addition to the sampling hardware, a single-use disposable silicon mask affixed with a filter is required for each exhaled breath collection. To reduce the financial burden, streamline device upkeep, reduce waste material, and ease the logistical burden associated with the single use masks, it is hypothesized that the consumable masks and filters could be sterilized by autoclaving for reuse. The masks were contaminated, autoclaved, and then tested for any surviving pathogens with spore strip standards and by measuring the optical density of cultures. The compound background collected when using the ReCIVA with new masks was compared to that collected with repeatedly autoclaved masks via thermal desorption gas chromatography mass spectrometry (TD-GC-MS). The capacity to block particulate matter of new filters was tested against that of autoclaved filters by introducing an aerosol and comparing pre-filter and post-filter particle counts. Finally, breath samplings were conducted with new masks and autoclaved masks to test for changes in measurements by TD-GC-MS of exogenous and endogenous compounds. The data illustrate the autoclave cycle sterilizes masks spiked with saliva to background levels (p= 0.2527). The results indicate that background levels of siloxane compounds are increased as masks are repetitively autoclaved. The data show that mask filters have significant breakthrough of 1µm particles after five repetitive autoclaving cycles compared to new filters (p= 0.0219). Finally, exhaled breath results utilizing a peppermint ingestion protocol indicate two compounds associated with peppermint, menthone and 1-Methyl-4-(1-methylethyl)-cyclohexanol, and an endogenous exhaled breath compound, isoprene, show no significant difference if sampled with a new mask or a mask autoclaved five times (p> 0.1063). Collectively, the data indicate that ReCIVA masks and filters can be sterilized via autoclave and reused. The results suggest ReCIVA mask and filter reuse should be limited to three times to limit potentially problematic background contaminants and filter dysfunction.

Effects of a mobile health nutrition intervention on dietary intake in children who have autism spectrum disorder.

Background: Children who have Autism Spectrum Disorder (ASD) show preferences for processed foods, such as salty and sugary snacks (SSS) and sugar-sweetened beverages (SSB), while healthier foods, such as fruits and vegetables (FV), are consumed less. Innovative tools are needed that can efficiently disseminate evidence-based interventions and engage autistic children to improve their diet. Aim: The aim of this 3-month randomized trial was to test the initial efficacy of a mobile health (mHealth) nutrition intervention on changing consumption of targeted healthy (FV) and less healthy foods/beverages (SSS, SSB) in children who have ASD, ages 6-10, who were picky eaters. Methods: Thirty-eight parent-child dyads were randomly assigned to either an intervention (technology) group or a wait list control (education) group. The intervention included behavioral skills training, a high level of personalization for dietary goals, and involved parents as "agents of change." Parents in the education group received general nutrition education and the dietary goals but did not receive skills training. Children's intake was assessed at baseline and at 3 months using 24-hour dietary recalls. Results: While there were no significant group-by-time interactions (P > 0.25) for any of the primary outcomes, we found a significant main effect of time for FV intake (P = 0.04) indicating that both groups consumed more FV at 3 months (2.58 ± 0.30 servings/day) than at baseline (2.17 ± 0.28 servings/day; P = 0.03). Children in the intervention group who consumed few FV at baseline and showed high engagement with the technology increased their FV intake by 1.5 servings/day (P < 0.01). Children's taste/smell sensitivity significantly predicted their FV intake (P = 0.0446); for each unit of lower taste/smell sensitivity (indicating greater sensory processing abnormalities), FV intake increased by 0.13 ± 0.1 servings/day. Discussion: This mHealth intervention did not yield significant between-group differences for changing consumption of targeted foods/beverages. Only children who consumed few FV at baseline and highly engaged with the technology increased their FV intake at 3 months. Future research should test additional strategies to expand the intervention's impact on a wider range of foods while also reaching a broader group of children who have ASD. This trial was registered at clinicaltrials.gov as NCT03424811.Clinical Trial Registration: This study was registered at clinicaltrials.gov as NCT03424811.

Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist.

GDF15 and its receptor GFRAL/RET form a non-homeostatic system that regulates food intake and body weight in preclinical species. Here, we describe a GDF15 analog, LY3463251, a potent agonist at the GFRAL/RET receptor with prolonged pharmacokinetics. In rodents and obese non-human primates, LY3463251 decreased food intake and body weight with no signs of malaise or emesis. In a first-in-human study in healthy participants, single subcutaneous LY3463251 injections showed a safety and pharmacokinetic profile supporting further clinical development with dose-dependent nausea and emesis in a subset of individuals. A subsequent 12-week multiple ascending dose study in overweight and obese participants showed that LY3463251 induced significant decreases in food intake and appetite scores associated with modest body weight reduction independent of nausea and emesis (clinicaltrials.gov: NCT03764774). These observations demonstrate that agonism of the GFRAL/RET system can modulate energy balance in humans, though the decrease in body weight is surprisingly modest, suggesting challenges in leveraging the GDF15 system for clinical weight-loss applications.

Investigation of an individual with background levels of exhaled isoprene: a case study.

Isoprene is one of the most abundant and most frequently evaluated volatile organic compounds in exhaled breath. Recently, several individuals with background levels of exhaled isoprene have been identified. Here, case study data are provided for an individual, identified from a previous study, with this low prevalence phenotype. It is hypothesized that the individual will illustrate low levels of exhaled isoprene at rest and during exercise. At rest, the subject (7.1 ppb) shows background (µ= 14.2 ± 7.0 ppb) levels of exhaled isoprene while the control group illustrates significantly higher quantities (µ= 266.2 ± 72.3 ppb) via proton transfer reaction mass spectrometry (PTR-MS). The result, background levels of isoprene at rest, is verified by thermal desorption gas chromatography mass spectrometry (TD-GC-MS) collections with the individual showing -3.6 ppb exhaled isoprene while the room background containedµ= -4.1 ± 0.1 ppb isoprene. As isoprene has been shown previously to increase at the initiation of exercise, exercise bike experiments were performed with the individual identified with low isoprene, yielding low and invariant levels of exhaled isoprene (µ= 6.6 ± 0.1 ppb) during the exercise while control subjects illustrated an approximate 2.5-fold increase (preµ= 286.3 ± 43.8 ppb, exerciseµ= 573.0 ± 147.8 ppb) in exhaled isoprene upon exercise start. Additionally, exhaled breath bag data showed a significant decrease in isoprene (delta post/pre, p = 0.0078) of the control group following the exercise regimen. Finally, TD-GC-MS results for exhaled isoprene from the individual's family (mother, father, sister and maternal grandmother) illustrated that the mother and father exhibited isoprene values (28.5 ppb, 77.2 ppb) below control samples 95% confidence interval (µ= 166.8 ± 43.3 ppb) while the individual's sister (182.0 ppb) was within the control range. These data provide evidence for a large dynamic range in exhaled isoprene in this family. Collectively, these results provide additional data surrounding the existence of a small population of individuals with background levels of exhaled isoprene.

Low level lead exposure in early childhood and parental education on adolescent IQ and working memory: a cohort study.

BACKGROUND: The independent effect of lead exposure and parental education on children's neurocognition is well-documented. However, few studies have examined the combined effect of childhood lead exposure and parental education on adolescent neurocognition, especially in China. OBJECTIVE: Examine both the combined and interactive effect of childhood blood lead levels (BLLs) and parental education on early adolescent neurocognition. METHODS: 417 children from a longitudinal cohort study in Jintan, China had BLLs measured at 3-5 years and 12 years, parental education levels assessed at 3-5 years, and neurocognitive outcomes tested at 12 years. RESULTS: BLLs at 3-5 years were inversely associated with adolescent IQ (ß -0.55 95% CI: -0.97, -0.13) but not working memory (ß -0.06 95% CI: -0.23, 0.11) and parental education was positively associated with adolescent IQ (ß 0.68 95% CI: 0.19, 1.17) and working memory (ß 0.24 95% CI: 0.04, 0.44). BLLs and parental education evidenced combined effects on neurocognition, where children with higher BLLs and lower fathers' education had mean IQ scores 7.84 (95% CI: -13.15, -2.53) points lower than children with lower BLLs and higher fathers' education. There were significant associations between parental education and working memory, however, not with BLLs. The interaction between mother and father high school education and BLLs was insignificant for effects on IQ and working memory. SIGNIFICANCE: Childhood lead exposure and parental education levels have a combined and long-term impact on IQ, evidence that may partially explain disparities in lead exposure associated outcomes and highlight those children at greatest risk for neurocognitive deficits. IMPACT STATEMENT: Children continue to be exposed to low-levels of environmental lead in China and globally, warranting examination of the impact of such exposures. This paper demonstrates that even relatively low-level lead exposure in early childhood significantly influences adolescent neurocognitive functioning. Furthermore, co-existing social determinant of health-related variables, measured here as parental education, have a combined impact on neurocognition. These results highlight children at greater risk for neurocognitive deficits and demonstrate the need to examine the influence of lead exposure within the broader socio- ecological environment, as these factors work in tandem to influence longer-term neurocognitive outcomes.

Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents.

AIM: To investigate the role of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists alone or combined with glucagon-like peptide-1 receptor (GLP-1R) agonists to regulate palatable food intake and the role of specific macronutrients in these preferences. METHODS: To understand this regulation, we treated mice and rats on several choice diet paradigms of chow and a palatable food option with individual or dual GIPR and GLP-1R agonists. RESULTS: In mice, the dual agonist tirzepatide suppressed total caloric intake, while promoting the intake of chow over a high fat/sucrose diet. Surprisingly, GIPR agonism alone did not alter food choice. The food intake shift observed with tirzepatide in wild-type mice was completely absent in GLP-1R knockout mice, suggesting that GIPR signalling does not regulate food preference. Tirzepatide also selectively suppressed the intake of palatable food but not chow in a rat two-diet choice model. This suppression was specific to lipids, as GLP-1R agonist and dual agonist treatment in rats on a choice paradigm assessing individual palatable macronutrients robustly inhibited the intake of Crisco (lipid) without decreasing the intake of a sucrose (carbohydrate) solution. CONCLUSIONS: Decreasing preference for high-caloric, high-fat foods is a powerful action of GLP-1R and dual GIPR/GLP-1R agonist therapeutics, which may contribute to the weight loss success of these drugs.

EGR3 regulates opioid-related nociception and motivation in male rats.

Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund's adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors.

Longitudinal association of early childhood lead exposure and adolescent heart rate variability: influence of parental education.

Lead exposure has been shown to dysregulate physiological stress responses. However, few studies have investigated the effect of lead exposure on later heart rate variability (HRV), an indicator of a stress response, in large samples of children. Furthermore, the interaction between social environmental factors and lead exposure in childhood, which commonly co-occur, remains understudied. This study examined relationships between childhood lead exposure and early adolescent physiological stress responses at different levels of parental education. Participants were 406 children from Jintan, China. Blood lead levels (BLLs) and parental education data were collected at 3-5 years of age, and HRV outcomes assessed at 12 years via frequency domain measures (LF/HF ratio) collected during an induced stress test. Results show a significant interaction between parental education and BLLs at 3-5 years. This relationship was found to be most consistent for the interaction between BLLs and mother's years of education for both the planning (ß = 0.12, p = 0.046) and speaking (ß = 0.11, p = 0.043) phase of the stress task, suggesting that increasing years of mother's education may enhance the deleterious influence of lead exposure on the HRV frequency measure, LF/HF ratio. This research highlights the complexity in lead exposure induced outcomes.

Pharmacological Evaluation of a Pegylated Urocortin-1 Peptide in Experimental Autoimmune Disease Models.

Urocortin-1 (UCN1) is a member of the corticotropin releasing hormone (CRH) family of peptides that acts through CRH-receptor 1 (CRHR1) and CRH-receptor 2 (CRHR2). UCN1 can induce the adrenocorticotropin hormone and downstream glucocorticoids through CRHR1 and promote beneficial metabolic effects through CRHR2. UCN1 has a short half-life and has been shown to improve experimental autoimmune disease. A pegylated UCN1 peptide (PEG-hUCN1) was generated to extend half-life and was tested in multiple experimental autoimmune disease models and in healthy mice to determine effects on corticosterone induction, autoimmune disease, and glucocorticoid induced adverse effects. Cardiovascular effects were also assessed by telemetry. PEG-hUCN1 demonstrated a dose dependent 4-6-fold elevation of serum corticosterone and significantly improved autoimmune disease comparable to prednisolone in several experimental models. In healthy mice, PEG-hUCN1 showed less adverse effects compared with corticosterone treatment. PEG-hUCN1 peptide induced an initial 30% reduction in blood pressure that was followed by a gradual and sustained 30% increase in blood pressure at the highest dose. Additionally, an adeno-associated viral 8 (AAV8) UCN1 was used to assess adverse effects of chronic elevation of UCN1 in wild type and CRHR2 knockout mice. Chronic UCN1 expression by an AAV8 approach in wild type and CRHR2 knockout mice demonstrated an important role of CRHR2 in countering the adverse metabolic effects of elevated corticosterone from UCN1. Our findings demonstrate that PEG-hUCN1 shows profound effects in treating autoimmune disease with an improved safety profile relative to corticosterone and that CRHR2 activity is important in metabolic regulation. SIGNIFICANCE STATEMENT: This study reports the generation and characterization of a pegylated UCN1 peptide and the role of CRHR2 in UCN1-induced metabolic effects. The potency/selectivity, pharmacokinetic properties, pharmacodynamic effects, and efficacy in four autoimmune models and safety profiles are presented. This pegylated UCN1 shows potential for treating autoimmune diseases with reduced adverse effects compared to corticosterone treatment. Continuous exposure to UCN1 through an AAV8 approach demonstrates some glucocorticoid mediated adverse metabolic effects that are exacerbated in the absence of the CRHR2 receptor.

Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide.

BACKGROUND AND OBJECTIVE: Tirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function. METHODS: Participants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration-time curve from zero to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability. RESULTS: Tirzepatide exposure, based on AUC0-∞ and Cmax, was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC0-∞ or Cmax between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC0-∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and Cmax ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to Cmax of tirzepatide across all groups (time to Cmax median difference vs control [90% CI]: 0 [- 4.00, 12.00], 0 [- 12.00, 12.00], and 0 [- 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC0-∞, Cmax, and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants. CONCLUSIONS: Tirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03940742.

High Depressive Symptoms, Low Family Functioning, and Low Self-Efficacy in Mothers of Children With Autism Spectrum Disorder Compared to Two Control Groups.

BACKGROUND: Parents of children with autism spectrum disorder (ASD) face unique challenges in raising their children, and they are at higher risk for depression compared to parents of children with typical development (TD) and other disabilities. AIMS: (1) To compare prevalence of depressive symptoms among mothers of children with ASD (n = 101), Down syndrome (DS, n = 101), and TD (n = 43) and (2) to describe the relationships among depression, self-efficacy, and family functioning, and describe the mediating role of maternal child care self-efficacy between depressive symptoms and child behavior. METHODS: In this cross-sectional study, mothers completed the Social Communication Questionnaire, Aberrant Behavior Checklist, Patient Health Questionnaire-9 (PHQ-9), Family Assessment Device General Functioning Scale, and Maternal Self-Efficacy Scale. RESULTS: Mothers of children with ASD had significantly higher mean PHQ-9 scores (p < .001), higher proportion of positive depression screening (p < .001), and lower family functioning (p < .001). Better family functioning is associated with less depression, better self-efficacy, and less severe ASD symptoms and behaviors. Self-efficacy mediated the relationship between depression and child ASD symptoms, and problematic behavior. CONCLUSIONS: The rates of reported history of depression and low family functioning in mothers of children with ASD are twice the rate in mothers of children with DS and TD. Maternal child care self-efficacy is protective against maternal depression, even in the presence of severe child problematic behaviors and ASD symptoms. Interventions that increase child care self-efficacy and family functioning may be helpful in addressing depression in mothers of children with ASD.

Characterizing opioid prescribing to adolescents at time of discharge from a pediatric hospital over a five-year period.

PURPOSE: To characterize opioid prescribing over a 5-year period to adolescents upon discharge from one urban pediatric medical center. DESIGN AND METHODS: A retrospective cross-sectional analysis of 4354 adolescents discharged with a pain medication after an admission of ≤5 days between January 2015 and December 2019 was performed. Two outcome groups, based on the analgesics prescribed at discharge, were compared: those discharged with a prescription for a non-opioid only and those discharged with an opioid prescription. The association between year of discharge and receipt of opioid, while adjusting for relevant demographic and clinical characteristics, was also explored. RESULTS: Approximately 64% of the sample was discharged with an opioid prescription. Of those, the median daily dosage was 45.0 morphine milligram equivalents (MME) [IQR: 32.4, 45.0]. Year of discharge was associated with decreased odds of receiving an opioid when adjusting for age, race, sex, insurance, pain scores, opioid exposure during hospitalization, length of stay, and undergoing surgery. The odds of being discharged with an opioid decreased each year by 29% (Adjusted Odds Ratio [AOR] = 0.71, CI:0.68-0.73). Concurrently, the proportion of patients discharged with nonopioid pain medication increased from 25% of adolescent patients in 2015 to 50% in 2019. CONCLUSIONS: Overall, opioid prescribing to adolescents at time of discharge decreased over time in our sample. PRACTICE IMPLICATIONS: While prescribing has decreased opioid analgesics are dispensed to young patients. Risk of opioid use disorder and overdose is rare in this population, but adolescence is good opportunity for nursing to promote safe prescribing and analgesic use.

Absorption, Distribution, Metabolism, and Excretion of Therapeutic Proteins: Current Industry Practices and Future Perspectives.

Therapeutic proteins (TPs) comprise a variety of modalities, including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to their large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subject to different absorption, distribution, metabolism, and excretion (ADME) processes as compared with small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group was sponsored by the Translational and ADME Sciences Leadership Group within the Innovation and Quality (IQ) consortium with objectives to: (1) better understand the current practices of ADME data generated for TPs across IQ member companies, (2) learn about their regulatory strategies and interaction experiences, and (3) provide recommendations on best practices for conducting ADME studies for TPs. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to the U.S. Food and Drug Administration was also collated by reviewing regulatory submission packages of TPs approved between 2011 and 2020. This article summarizes the key learnings from the survey and an overview of ADME data presented in biologics license applications along with future perspectives and recommendations for conducting ADME studies for internal decision-making as well as regulatory submissions for TPs. SIGNIFICANCE STATEMENT: This article provides comprehensive assessment of the current practices of absorption, distribution, metabolism, and excretion (ADME) data generated for therapeutic proteins (TPs) across the Innovation and Quality participating companies and the utility of the data in discovery, development, and regulatory submissions. The TP ADME working group also recommends the best practices for condu-cting ADME studies for internal decision-making and regulatory submissions.

Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats.

Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder. Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain regions, particularly the VTA. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. Attenuation of H3Q5dop during abstinence induced persistent changes in gene expression programs associated with neuronal signaling and dopaminergic function in heroin abstinence and led to reduced heroin-seeking behavior. Interestingly, the observed changes in molecular pathways after heroin SA showed significant yet reversed overlap with the same genes altered in cocaine SA. These findings establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in heroin-induced functional plasticity in VTA.

Early childhood lead exposure and adolescent heart rate variability: A longitudinal cohort study.

Lead is a known neurotoxicant with many detrimental health effects, including neurocognitive deficits and cardiovascular and metabolic disorders. However, few studies have tested the association between lead exposure and the physiological stress response, which in and of itself may act as a precursor to and/or underlying mechanism of detrimental health outcomes. The purpose of this study was to examine the influence of early childhood and early adolescent low-level lead exposure on early adolescent heart rate variability, a widely-used measure of physiological stress. Participants were 408 children from Jintan, China for whom blood lead levels were measured between 3 and 5 years (early childhood) and again at 12 years (early adolescence). Heart rate variability was assessed at 12 years while participants underwent an induced stress task utilizing the ratio of low to high frequency (LF/HF) ECG measures. Mean blood lead levels in the cohort were 6.63 mcg/dl and 3.10 mcg/dl at 3-5 years and 12 years, respectively. Blood lead levels at 3-5 years of age (ß 0.06, p = 0.027), but not at age 12 (ß -0.05, p = 0.465), were significantly associated with LF/HF measures while controlling for multiple sociodemographic variables, potentially reflecting a dysregulated stress response with a shift towards sympathetic dominance. These findings suggest that early childhood lead exposure may have a detrimental influence on early adolescent autonomic responses to acute stress, which holds implications for cardiovascular health and overall growth and development.

The Impact of Nutritional Supplementation on Sweat Metabolomic Content: A Proof-of-Concept Study.

Sweat is emerging as a prominent biosource for real-time human performance monitoring applications. Although promising, sources of variability must be identified to truly utilize sweat for biomarker applications. In this proof-of-concept study, a targeted metabolomics method was applied to sweat collected from the forearms of participants in a 12-week exercise program who ingested either low or high nutritional supplementation twice daily. The data establish the use of dried powder mass as a method for metabolomic data normalization from sweat samples. Additionally, the results support the hypothesis that ingestion of regular nutritional supplementation semi-quantitatively impact the sweat metabolome. For example, a receiver operating characteristic (ROC) curve of relative normalized metabolite quantities show an area under the curve of 0.82 suggesting the sweat metabolome can moderately predict if an individual is taking nutritional supplementation. Finally, a significant correlation between physical performance and the sweat metabolome are established. For instance, the data illustrate that by utilizing multiple linear regression modeling approaches, sweat metabolite quantities can predict VO2 max (p = 0.0346), peak lower body Windage (p = 0.0112), and abdominal circumference (p = 0.0425). The results illustrate the need to account for dietary nutrition in biomarker discovery applications involving sweat as a biosource.

Science and Technology Solutions for Scalable SARS-CoV-2 Testing to Inform Return to Full Capacity Strategy in United States Air Force Workforce Personnel.

SARS-CoV-2 has highlighted the requirement for a drastic change in pandemic response. While cases continue to rise, there is an urgent need to deploy sensitive and rapid testing in order to identify potential outbreaks before there is an opportunity for further community spread. Currently, reverse transcription quantitative polymerase chain reaction (RT-qPCR) is considered the gold standard for diagnosing an active infection, using a nasopharyngeal swab; however, it can take days after symptoms develop to properly identify and trace the infection. While many civilian jobs can be performed remotely, the Department of Defense (DOD) is by nature a very fluid organization which requires in-person interaction and a physical presence to maintain effectiveness. In this commentary, we examine several current and emergent technologies and their ability to identify both active and previous SARS-CoV-2 infection, possibly in those without symptoms. Further, we will explore an ongoing study at the Air Force Research Laboratory, utilizing Reverse Transcription Loop-mediated isothermal amplification (RT-LAMP), next-generation sequencing, and the presence of SARS-CoV-2 antibodies through Lateral Flow Immunoassays. The ability to identify SARS-CoV-2 through volatile organic compound biomarker identification will also be explored. By exploring and validating multiple testing strategies, and contributing to Operation Warp Speed, the DOD is postured to respond to SARS-CoV-2, and future pandemics.