Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders.

INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.

Quinolinic acid links kidney injury to brain toxicity.

Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 ( Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a novel connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells adjacent to the ventricle in the setting of kidney failure. These findings were associated with brain inflammation and cell death. A separate mouse model of acute kidney injury also had an increase in circulating toxic tryptophan metabolites along with altered brain inflammation. Patients with advanced CKD similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life in humans. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.

Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

Churn in Supplemental Nutrition Assistance Program: Changes in Medicaid Expenditure and Acute Care Utilization.

BACKGROUND: The Supplemental Nutrition Assistance Program (SNAP) provides financial assistance to low-income individuals and families to help them purchase food. However, when participants experience short-term disenrollment from the program, known as churn, it can disrupt their health care usage patterns or result in acute health care needs due to the loss of financial benefits and time burden required to reapply for SNAP. OBJECTIVE: The objective of this study was to examine the changes in health care expenditures and acute care utilization during periods of SNAP churn compared with nonchurn periods among those who churn during the study period. RESEARCH DESIGN: Longitudinal analysis of Pennsylvania Medicaid claims data for enrollees participating in SNAP between 2016 and 2018 using individual fixed-effects models. We add to the literature by estimating whether these changes varied based on the amount of SNAP benefit lost, or differed between adults and children. RESULTS: We found that SNAP churn was associated with reductions in pharmacy and primary care spending across all SNAP benefit levels and age groups. Specifically, our findings indicate a reduction of 4%-6% in pharmacy expenditures for adults and 2%-4% for children. Moreover, there was a 3%-4% decrease in primary care expenditures for adults and a 4%-6% decrease for children. Acute care utilization did not significantly change during a SNAP churn period. CONCLUSION: Our findings of decreases in pharmacy and primary care spending suggest that preventing SNAP churn may help reduce instances where adult and child participants forgo necessary care.

The Influence of Branched-Chain Amino Acid Supplementation on Fatigue and Tryptophan Metabolism After Acute and Chronic Exercise in Older Adults: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Fatigue is a strong predictor of negative health outcomes in older adults. Kynurenine, a metabolite of tryptophan, is strongly associated with fatigue. Reductions in fatigue are observed with exercise; however, exercise training does not completely alleviate symptoms. Branched-chain amino acids (BCAAs) have been shown to have advantageous effects on exercise performance and compete with kynurenine for transport into the central nervous system. Thus, the combination of BCAA and exercise may exert synergized effects of mental and physical fatigue. Therefore, we hypothesize that BCAA added to exercise will shift kynurenine metabolism toward enhanced synthesis of kynurenic acid, thereby reducing fatigue. OBJECTIVE: This randomized, double-blind, placebo-controlled trial aims to compare the effects of acute (approximately 45 min) and chronic (8 wk) exercise with and without BCAA supplementation on mental and physical fatigue and assess whether the hypothesized outcomes are modulated by changes in kynurenine metabolism in 30 older adults (n=15, 50% per group). METHODS: Older adults (aged 60-80 y) who do not exercise >2 days per week and self-report fatigue (≥3 on a scale of 1-10) will be recruited. Participants will be randomized to either the exercise+BCAA group or exercise+placebo group. Participants will engage in high-volume, moderate-intensity, whole-body exercise training (aerobic and resistance exercise; either in-person or web-based sessions) 3 times per week for 8 weeks. In addition, participants will consume daily either 100 mg/kg body weight of BCAA (2:1:1 leucine:isoleucine:valine) or placebo (maltodextrin) throughout the 8-week intervention. BCAA and placebo powders will be identical in color and dissolved in 400 mL of water and 2.5 g of a calorie-free water flavor enhancer. Muscle biopsies will be collected before and after the intervention after a 12-hour fast to examine changes in the biomarkers of tryptophan metabolism and inflammation. Our primary outcomes include changes in mental and physical fatigue and metabolism after the 8-week exercise training between the 2 groups. Mental and physical fatigue will be measured before and after the intervention. Mental fatigue will be subjectively assessed through the completion of validated questionnaires. Physical fatigue will be measured by isometric handgrip, 1-repetition maximum, chair rise, 400-meter walk, and cardiopulmonary exercise tests. RESULTS: The study was funded in March 2022, with an anticipated projected data collection period lasting from January 2023 through December 2023. CONCLUSIONS: The discovery that kynurenine concentrations are associated with fatigue and are responsive to BCAA supplementation during exercise training could have important implications for the development of future interventions, both lifestyle and pharmacologic, to treat fatigue in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT05484661; https://www.clinicaltrials.gov/study/NCT05484661. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52199.

Association Between Hospital Adoption of an Emergency Department Treatment Pathway for Opioid Use Disorder and Patient Initiation of Buprenorphine After Discharge.

Importance: Emergency department (ED)-based initiation of buprenorphine has been shown to increase engagement in outpatient treatment and reduce the risk of subsequent opioid overdose; however, rates of buprenorphine treatment in the ED and follow-up care for opioid use disorder (OUD) remain low in the US. The Opioid Hospital Quality Improvement Program (O-HQIP), a statewide financial incentive program designed to increase engagement in OUD treatment for Medicaid-enrolled patients who have ED encounters, has the potential to increase ED-initiated buprenorphine treatment. Objective: To evaluate the association between hospitals attesting to an ED buprenorphine treatment O-HQIP pathway and patients' subsequent initiation of buprenorphine treatment. Design, Setting, and Participants: This cohort study included Pennsylvania patients aged 18 to 64 years with continuous Medicaid enrollment 6 months before their OUD ED encounter and at least 30 days after discharge between January 1, 2016, and December 31, 2020. Patients with a claim for medication for OUD 6 months before their index encounter were excluded. Exposures: Hospital implementation of an ED buprenorphine treatment O-HQIP pathway. Main Outcomes and Measures: The main outcome was patients' receipt of buprenorphine within 30 days of their index OUD ED visit. Between August 2021 and January 2023, data were analyzed using a difference-in-differences method to evaluate the association between hospitals' O-HQIP attestation status and patients' treatment with buprenorphine after ED discharge. Results: The analysis included 17 428 Medicaid-enrolled patients (female, 43.4%; male, 56.6%; mean [SD] age, 37.4 [10.8] years; Black, 17.5%; Hispanic, 7.9%; White, 71.6%; other race or ethnicity, 3.0%) with OUD seen at O-HQIP-attesting or non-O-HQIP-attesting hospital EDs. The rate of prescription fills for buprenorphine within 30 days of an OUD ED discharge in the O-HQIP attestation hospitals before the O-HQIP intervention was 5%. The O-HQIP attestation was associated with a statistically significant increase (2.6 percentage points) in prescription fills for buprenorphine within 30 days of an OUD ED discharge (ß, 0.026; 95% CI, 0.005-0.047). Conclusions and Relevance: In this cohort study, the O-HQIP was associated with an increased initiation of buprenorphine in patients with OUD presenting to the ED. These findings suggest that statewide incentive programs may effectively improve outcomes for patients with OUD.

Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.

Randomization to Treadmill Training Improves Physical and Metabolic Health in Association With Declines in Oxidative Stress in Stroke.

OBJECTIVE: To investigate the effect of aerobic exercise vs control (stretching/balance) on inflammatory and oxidative stress biomarkers in stroke survivors and whether these changes are associated with improvements in physical and metabolic health. DESIGN: Randomized controlled trial. SETTING: The general communities of Baltimore, Maryland, and Atlanta, Georgia. PARTICIPANTS: Two hundred forty-six older (>50 years), chronic (>6 months) survivors of stroke (N=246) with hemiparetic gait were recruited, with 51 completing pre-intervention testing and 39 completing postintervention testing. Participants were required to have completed all conventional physical therapy and be capable of walking 3 minutes on a treadmill (N=246). INTERVENTION: Participants completed 6 months of 2 times/wk stretching or balance (ST; n=19) or 3 times/wk aerobic treadmill rehabilitation (TM; n=20;). MAIN OUTCOME MEASURE(S): Peak oxygen uptake rate (V̇o2peak), 6-minute walking distance (6MWD), fasting plasma glucose, insulin, oxidative stress, and inflammatory biomarkers were assessed pre- and postintervention. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. RESULTS: Physical function and metabolic health parameters tended to improve after TM but not ST (ST vs TM: V̇o2peak: -9% vs 24%, P<.01; 6MWD: 1% vs 15%, P=.05; insulin: -1% vs -31%, P=.05; HOMA-IR: -3% vs -29%, P=.06). Plasma concentrations of nitrotyrosine, protein carbonyls, and oxidized low-density lipoprotein (oxLDL) tended to decrease from pre-intervention concentrations in response to TM compared to ST (ST vs TM: nitrotyrosine: 2% vs -28%, P=.01; protein carbonyls: -4% vs -34%, P=.08; oxLDL: -3% vs -32%, P<.01). Changes in circulating concentrations of C-reactive protein, protein carbonyls, and oxLDL were negatively associated with changes in V̇o2peak and 6MWD (r's=-0.40 to -0.76) and positively associated with fasting plasma insulin and HOMA-IR (r's=0.52-0.81, Ps<.01). CONCLUSIONS: Six months of TM tends to be associated with increased functional capacity and reduced oxidative stress in chronic stroke survivors. Our findings identify potentially modifiable systemic markers of inflammation and oxidative stress important to stroke rehabilitation and provide potential targets for novel therapeutics in future studies.

Kynurenine Metabolism as a Mechanism to Improve Fatigue and Physical Function in Postmenopausal Breast Cancer Survivors Following Resistance Training.

This pilot examines whether resistance training (RT) can induce changes in kynurenine (KYN) metabolism, which may contribute to improved physical function in breast cancer survivors (BCSs). Thirty-six BCSs (63.2 ± 1.1 years) underwent assessments of physical function and visual analog scale (100 cm) fatigue and quality of life before and after 12 weeks of RT (N = 22) or non-exercise control (CBCT©: Cognitively Based Compassion Training, N = 10). Blood was collected before and after interventions for assessment of KYN, kynurenic acid (KYNA), and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). At baseline, the women were moderately fatigued (mean score: 46 cm) and at risk of poor functional mobility. A group*time interaction was observed for all measures of strength with improvements (~25−35%) following RT (p's < 0.01), but not CBCT. Time effects were observed for fatigue (−36%) and quality of life (5%) (p's < 0.01), where both groups improved in a similar manner. A group*time interaction was observed for KYN (p = 0.02) and PGC-1α (p < 0.05), with KYN decreasing and PGC-1α increasing following RT and the opposite following CBCT. These changes resulted in KYN/KYNA decreasing 34% post-RT, but increasing 21% following CBCT. These data support RT as a therapeutic intervention to counteract the long-term side effect of fatigue and physical dysfunction in BCSs. Additionally, the results suggest that this effect may be mediated through the activation of PGC-1α leading to alterations in KYN metabolism.

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.

Suicidal Ideation Across Three Timepoints in Patients Discharged from Psychiatric Hospitalization.

This article describes the rate of suicidal ideation (SI) across three timepoints among treatment-seeking patients recently discharged from psychiatric hospitalization-a group that is at ultrahigh-risk for suicide. Retrospective chart review was used to quantify the rate of SI in 252 consecutive patients discharged to a post-hospital mental health clinic. Data include patients' lifetime history of SI, SI at the time of hospital intake, and SI at post-hospital outpatient clinic intake, as well as demographics and diagnosis. Overall, 67% of the sample reported a lifetime history of SI, 49% reported SI during hospital intake, and 6% reported SI at post-hospital clinic intake. Age was the only variable associated with history of SI (p = .04), with younger patients more likely (OR = 1.85) to report a history of SI. These results may help inform the development of interventions for the population of ultrahigh-risk patients being discharged from hospital after psychiatric care.

Clinical Evaluation of a Novel CGM-Informed Bolus Calculator with Automatic Glucose Trend Adjustment.

Background: Expert opinion guidelines and limited data from clinical trials recommend adjustment to bolus insulin doses based on continuous glucose monitor (CGM) trend data, yet minimal evidence exists to support this approach. We performed a clinical evaluation of a novel CGM-informed bolus calculator (CIBC) with automatic insulin bolus dose adjustment based on CGM trend used with sensor-augmented pump therapy. Materials and Methods: In this multicenter, outpatient study, participants 6-70 years of age with type 1 diabetes (T1D) used the Omnipod® 5 System in Manual Mode, first for 7 days without a connected CGM (standard bolus calculator, SBC, phase 1) and then for 7 days with a connected CGM using the CIBC (CIBC phase 2). The integrated bolus calculator used stored pump settings plus user-estimated meal size and/or either a manually entered capillary glucose value (SBC phase) or an imported current CGM value and trend (CIBC phase) to recommend a bolus amount. The CIBC automatically increased or decreased the suggested bolus amount based on the CGM trend. Results: Twenty-five participants, (mean ± standard deviation) 27 ± 15 years of age, with T1D duration 12 ± 9 years and A1C 7.0% ± 0.9% completed the study. There were significantly fewer sensor readings <70 mg/dL 4 h postbolus with the CIBC compared to the SBC (2.1% ± 2.0% vs. 2.8 ± 2.7, P = 0.03), while percent of sensor readings >180 and 70-180 mg/dL remained the same. There was no difference in insulin use or number of boluses given between the two phases. Conclusion: The CIBC was safe when used with the Omnipod 5 System in Manual Mode, with fewer hypoglycemic readings in the postbolus period compared to the SBC. This trial was registered at ClinicalTrials.gov (NCT04320069).

Brain derived neurotrophic factor deficiency exacerbates inflammation-induced anhedonia in mice.

Brain-derived neurotrophic factor (BDNF) is implicated in the pathology of major depression and influences the inflammatory response. Prolonged immune system activation can cause depression symptoms, and individuals with low BDNF expression may be vulnerable to inflammation-induced depression. We tested the hypothesis that BDNF deficient mice are vulnerable to the induction of depressive-like behavior following peripheral immune challenge. BDNF heterozygous (BDNF+/-) or wild-type (BDNF+/+) littermate mice were injected intraperitoneally (i.p.) with endotoxin (lipopolysaccharide, LPS) to trigger an acute pro-inflammatory response. After resolution of the acute sickness response, central expression of inflammatory genes, kynurenine metabolites, and depressive-like behaviors across multiple dimensions (symptoms) were measured. BDNF+/- mice displayed an exaggerated neuroinflammatory response following peripheral immune challenge. Pro-inflammatory cytokines interleukin-1ß (IL-1ß), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) were overexpressed in BDNF+/- mice relative to BDNF+/+ littermate control mice. While behavioral despair and anxiety-like behavior was not different between genotypes, LPS-induced anhedonia-like behavior was significantly more pronounced in BDNF+/- mice relative to BDNF+/+ mice. The kynurenine pathway mediates the many depressive-like behavioral effects of peripheral LPS, and similar to pro-inflammatory cytokine gene expression, indoleamine 2,3-dioxygenase (IDO) expression and kynurenine metabolism was exaggerated in BDNF+/- mice. Genetic BDNF deficiency results in a dysregulated neuroinflammatory and metabolic response to peripheral immune challenge and in a specific vulnerability to the development of inflammation-induced anhedonia.

Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation.

Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.

Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications.

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that 'fuel the fire' in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

Chronic Unpredictable Stress Alters Brain Tryptophan Metabolism and Impairs Working Memory in Mice without Causing Depression-Like Behaviour.

Chronic stress is a well-known risk factor in major depressive disorder and disrupts the kynurenine and serotonin pathways of tryptophan metabolism. Here, we characterize the temporal central and peripheral changes in tryptophan metabolism and concomitant depressive-like behavioural phenotype induced during the progression of chronic unpredictable stress (CUS). Mice were exposed to 0, 10, 20, or 30 days of CUS followed by a panel of behavioural assays to determine depressive-like phenotypes. Immediately after behavioural testing, plasma and brain tissue were collected for metabolic analysis. While anhedonia-like and anxiety-like behaviours were unaffected by stress, nesting behaviour and cognitive deficits became apparent in response to CUS exposure. While CUS caused a transient reduction in circulating quinolinic acid, no other tryptophan metabolites significantly changed in response to CUS. In the brain, tryptophan, kynurenine, picolinic acid, and 5-hydroxyindoleacetic acid concentrations were significantly elevated in CUS-exposed mice compared with non-stress control animals, while kynurenic acid, xanthurenic acid, and serotonin decreased in CUS-exposed mice. Metabolic turnover of serotonin to the major metabolite 5- hydroxyindoleacetic acid was markedly increased in response to CUS. These results suggest that CUS impairs hippocampal-dependent working memory and enhances nascent nesting behaviour in C57BL/6J male mice, and these behaviours are associated with increased brain kynurenine pathway metabolism leading to accumulation of picolinic acid and a significant reduction in serotonin levels.

First Outpatient Evaluation of a Tubeless Automated Insulin Delivery System with Customizable Glucose Targets in Children and Adults with Type 1 Diabetes.

Background: The objective of this study was to assess the safety and effectiveness of the first commercial configuration of a tubeless automated insulin delivery system, Omnipod® 5, in children (6-13.9 years) and adults (14-70 years) with type 1 diabetes (T1D) in an outpatient setting. Materials and Methods: This was a single-arm, multicenter, prospective clinical study. Data were collected over a 14-day standard therapy (ST) phase followed by a 14-day hybrid closed-loop (HCL) phase, where participants (n = 36) spent 72 h at each of three prespecified glucose targets (130, 140, and 150 mg/dL, 9 days total) then 5 days with free choice of glucose targets (110-150 mg/dL) using the Omnipod 5. Remote safety monitoring alerts were enabled during the HCL phase. Primary endpoints were difference in time in range (TIR) (70-180 mg/dL) between ST and HCL phases and proportion of participants reporting serious device-related adverse events. Results: Mean TIR was significantly higher among children in the free-choice period overall (64.9% ± 12.2%, P < 0.01) and when using a 110 mg/dL target (71.2% ± 10.2%, P < 0.01), a 130 mg/dL target (61.5% ± 7.7%, P < 0.01), and a 140 mg/dL target (64.8% ± 11.6%, P < 0.01), and among adults using a 130 mg/dL target (75.1% ± 11.6%, P < 0.05), compared to the ST phase (children: 51.0% ± 13.3% and adults: 65.6% ± 15.7%). There were no serious device-related adverse events reported during the HCL phase, nor were there episodes of severe hypoglycemia or diabetic ketoacidosis. Conclusion: The Omnipod 5 System was safe and effective when used at glucose targets from 110 to 150 mg/dL for 14 days at home in children and adults with T1D.

Branched-Chain Amino Acids Depletion during Hemodialysis Is Associated with Fatigue.

BACKGROUND: Fatigue is one of the most debilitating symptoms reported by maintenance hemodialysis (MHD) patients. Hemodialysis causes marked depletion in plasma essential amino acids. We studied the cross-sectional relationship of pre- and post-hemodialysis branched-chain amino acids (BCAAs) concentrations with fatigue in MHD patients. METHODS: MHD patients self-reported fatigue during a dialysis session using the Brief Fatigue Inventory. Pre- and post-dialysis plasma levels of BCAAs (valine, leucine, and isoleucine) were measured using HPLC-mass spectrometry. RESULTS: The mean age of study participants (n = 114) was 54.8 ± 12.8 years. Plasma levels of BCAAs decreased significantly post-dialysis compared to pre-dialysis (303.8 ± 9.4 vs. 392.1 ± 9.4 µM/L, p < 0.0001). Fatigue score increased as a function of age (p = 0.015). There was no association between pre-dialysis plasma levels of BCAAs and fatigue. A significant negative correlation was found between post-dialysis plasma levels of BCAAs and fatigue (p < 0.05). CONCLUSIONS: These preliminary findings suggest that disruption in BCAAs homeostasis may play a role in precipitating fatigue.

Non-toxic HSC Transplantation-Based Macrophage/Microglia-Mediated GDNF Delivery for Parkinson's Disease.

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.

Safety and Performance of the Omnipod Hybrid Closed-Loop System in Adults, Adolescents, and Children with Type 1 Diabetes Over 5 Days Under Free-Living Conditions.

Background: The objective of this study was to assess the safety and performance of the Omnipod® personalized model predictive control (MPC) algorithm in adults, adolescents, and children aged ≥6 years with type 1 diabetes (T1D) under free-living conditions using an investigational device. Materials and Methods: A 96-h hybrid closed-loop (HCL) study was conducted in a supervised hotel/rental home setting following a 7-day outpatient standard therapy (ST) phase. Eligible participants were aged 6-65 years with A1C <10.0% using insulin pump therapy or multiple daily injections. Meals during HCL were unrestricted, with boluses administered per usual routine. There was daily physical activity. The primary endpoints were percentage of time with sensor glucose <70 and ≥250 mg/dL. Results: Participants were 11 adults, 10 adolescents, and 15 children aged (mean ± standard deviation) 28.8 ± 7.9, 14.3 ± 1.3, and 9.9 ± 1.0 years, respectively. Percentage time ≥250 mg/dL during HCL was 4.5% ± 4.2%, 3.5% ± 5.0%, and 8.6% ± 8.8% per respective age group, a 1.6-, 3.4-, and 2.0-fold reduction compared to ST (P = 0.1, P = 0.02, and P = 0.03). Percentage time <70 mg/dL during HCL was 1.9% ± 1.3%, 2.5% ± 2.0%, and 2.2% ± 1.9%, a statistically significant decrease in adults when compared to ST (P = 0.005, P = 0.3, and P = 0.3). Percentage time 70-180 mg/dL increased during HCL compared to ST, reaching significance for adolescents and children: HCL 73.7% ± 7.5% vs. ST 68.0% ± 15.6% for adults (P = 0.08), HCL 79.0% ± 12.6% vs. ST 60.6% ± 13.4% for adolescents (P = 0.01), and HCL 69.2% ± 13.5% vs. ST 54.9% ± 12.9% for children (P = 0.003). Conclusions: The Omnipod personalized MPC algorithm was safe and performed well over 5 days and 4 nights of use by a cohort of participants ranging from youth aged ≥6 years to adults with T1D under supervised free-living conditions with challenges, including daily physical activity and unrestricted meals.