Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa.

Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.

γδ T cells: first line of defense and beyond.

γδ T cells, αß T cells, and B cells are present together in all but the most primitive vertebrates, suggesting that each population contributes to host immune competence uniquely and that all three are necessary for maintaining immune competence. Functional and molecular analyses indicate that in infections, γδ T cells respond earlier than αß T cells do and that they emerge late after pathogen numbers start to decline. Thus, these cells may be involved in both establishing and regulating the inflammatory response. Moreover, γδ T cells and αß T cells are clearly distinct in their antigen recognition and activation requirements as well as in the development of their antigen-specific repertoire and effector function. These aspects allow γδ T cells to occupy unique temporal and functional niches in host immune defense. We review these and other advances in γδ T cell biology in the context of their being the major initial IL-17 producers in acute infection.

Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology.

Organophosphate (OP) nerve agent (OPNA) intoxication leads to long-term brain dysfunctions. The ineffectiveness of current treatments for OPNA intoxication prompts a quest for the investigation of the mechanism and an alternative effective therapeutic approach. Our previous studies on 1400W, a highly selective inducible nitric oxide synthase (iNOS) inhibitor, showed improvement in epilepsy and seizure-induced brain pathology in rat models of kainate and OP intoxication. In this study, magnetic resonance imaging (MRI) modalities, behavioral outcomes, and biomarkers were comprehensively investigated for brain abnormalities following soman (GD) intoxication in a rat model. T1 and T2 MRI robustly identified pathologic microchanges in brain structures associated with GD toxicity, and 1400W suppressed those aberrant alterations. Moreover, functional network reduction was evident in the cortex, hippocampus, and thalamus after GD exposure, and 1400W rescued the losses except in the thalamus. Behavioral tests showed protection by 1400W against GD-induced memory dysfunction, which also correlated with the extent of brain pathology observed in structural and functional MRIs. GD exposure upregulated iron-laden glial cells and ferritin levels in the brain and serum, 1400W decreased ferritin levels in the epileptic foci in the brain but not in the serum. The levels of brain ferritin also correlated with MRI parameters. Further, 1400W mitigated the overproduction of nitroxidative markers after GD exposure. Overall, this study provides direct evidence for the relationships of structural and functional MRI modalities with behavioral and molecular abnormalities following GD exposure and the neuroprotective effect of an iNOS inhibitor, 1400W. SIGNIFICANT STATEMENT: Our studies demonstrate the MRI microchanges in the brain following GD toxicity, which strongly correlate with neurobehavioral performances and iron homeostasis. The inhibition of iNOS with 1400W mitigates GD-induced cognitive decline, iron dysregulation, and aberrant brain MRI findings.

An investment case analysis for the prevention and treatment of adolescent mental disorders and suicide in England.

BACKGROUND: Adolescent mental health (AMH) needs in England have increased dramatically and needs exceed treatment availability. This study undertook a comparative assessment of the health and economic return on investment (ROI) of interventions to prevent and treat mental disorders among adolescents (10-19 years) and examined intervention affordability and readiness. METHODS: Interventions were identified following a review of published and grey literature. A Markov model followed a simulated adolescent cohort to estimate implementation costs and health, education, and economic benefits. Intervention affordability was assessed, comparing annual cost per adolescent with NHS England per capita spending, and an expert panel assessed intervention readiness using a validated framework. RESULTS: Over 10- and 80-year horizons, interventions to treat mild anxiety and mild depression were most cost-effective, with the highest individual lifetime ROI (GBP 5822 GBP 1 and GBP 257: GBP 1). Preventing anxiety and depression was most affordable and 'implementation ready' and offered the highest health and economic benefits. A priority package (anxiety and depression prevention; mild anxiety and mild depression treatment) would avert 5 million disability-adjusted life-years (DALYS) and achieve an ROI of GBP 15: GBP 1 over 10 years or 11.5 million DALYs (ROI of GBP 55: GBP 1) over 80 years. CONCLUSION: The economic benefits from preventing and treating common adolescent mental disorders equivalent to 25% of NHS England's annual spending in 2021 over 10 years and 91% over 80 years. Preventing and early treatment for anxiety and depression had the highest ROIs and strong implementation readiness.

Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy.

BACKGROUND: Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs-atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for 3 days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure. METHODS: Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132 µg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m) and HI-6 (125 mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3 mg/kg, i.m.). An hour post-midazolam, 1400W (20 mg/kg, i.m.) or vehicle was administered daily for 2 weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays. RESULTS: We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20 min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68-positive glia) as a measure of neuroinflammation, and neurodegeneration (especially parvalbumin-positive neurons) in some brain regions. CONCLUSION: These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration (parvalbumin-positive neurons), and neuronal hyperexcitability.

Influence of Gestational Age, Secretor, and Lewis Blood Group Status on the Oligosaccharide Content of Human Milk.

OBJECTIVES: Human milk oligosaccharides (HMOs) are considered to play an important role for the infant. As the biotechnical production of some HMOs is feasible today and clinical studies are being designed, the individual variation of the total amount of HMOs and of single components is of particular importance. Our objectives were to investigate whether differences exist between term and preterm milk, milk from mothers with secretor or nonsecretor status, and a Lewis blood group (a+b-), (a-b+), or (a-b-) pattern. METHODS: Within a longitudinal study 96 milk samples (colostrum, transitional, and mature milk) from 32 mothers with preterm (n = 18) and term (n = 14) infants were collected. Delipidated and deproteinized milk was subjected to porous graphitized carbon cartridges followed by high pH anion exchange chromatography with pulsed amperometric detection. RESULTS: Quantitation of 16 single HMOs revealed changes during the first weeks of lactation without discrepancies between term and preterm milk. Significant differences occurred between "secretor" and "nonsecretor" milk (median approximately 10 vs 5 g/L total HMOs). Lacto-N-tetraose (LNT) and lacto-N-fucopentaose (LNFP) II comprised > 55% of the total HMO content in Lewis blood group (a+b-), "nonsecretor" milk and LNT together with 2'fucosyllactose, LNFP I, and difucosyllactose approximately 60% in Lewis (a-b+), "secretor" milk. In Lewis (a-b-), "secretor" milk 80% of oligosaccharides are due to LNT, 2'fucosyllactose, and LNFP I. CONCLUSIONS: There are marked differences in total HMOs and single HMOs in milk depending on Lewis blood group and secretor status, which need to be taken into account in clinical studies.

Ligand recognition during thymic development and gammadelta T cell function specification.

gammadelta T cells develop in the thymus before entering the periphery. Recent work suggests that thymic development does little to constrain gammadelta T cell antigen specificities, but instead determines their effector fate. When triggered through the T cell receptor, ligand-naïve gammadelta T cells produce IL-17, ligand-experienced cells make IFN-gamma and those that are strongly self-reactive make IL-4. Importantly, gammadelta T cells are able to make cytokines immediately upon TCR engagement. These characteristics allow gammadelta T cells to initiate an acute inflammatory response to pathogens and to host antigens revealed by injury. These advances warrant a fresh look at how gammadelta T cells may function in the immune system.

The return on investment for the prevention and treatment of childhood and adolescent overweight and obesity in China: a modelling study.

Background: The rapid increase in child and adolescent overweight and obesity (OAO) in China has a significant health and economic impact. This study undertook an investment case analysis to evaluate the health and economic impacts of child and adolescent OAO in China and the potential health and economic returns from implementing specific policies and interventions. Methods: The analysis estimates the reduction in mortality and morbidity from implementing a set of evidence-based interventions across China between 2025 and 2092 using a deterministic Markov cohort model. Modelled interventions were identified by literature review and expert recommendation and include fiscal and regulatory policies, eHealth breastfeeding promotion, school-based interventions, and nutritional counselling by physicians. The study applies a societal costing perspective to model the economic impact on healthcare cost savings, wages, and productivity during adulthood. By projecting and comparing the costs between a status quo scenario and an intervention scenario, the study estimates the return on investment (ROI) for interventions separately and in combination. Findings: Without intervention China will experience 3.3 billion disability-adjusted life years (DALYs) due its current levels of child and adolescent OAO and a lifetime economic impact of CNY 218 trillion (USD 31.6 trillion), or a lifetime CNY 2.5 million loss per affected child or adolescent (USD 350 thousand). National implementation of all five interventions would avert 179.4 million DALYs and result in CNY 13.1 trillion of benefits over the model cohort's lifetime. Implementing fiscal and regulatory policies had the strongest ROI, with benefits accruing at least 10 years after implementation. Scaling up China's current school-based interventions offers China significant health and economic gains, however, the ROI is lower than other modelled interventions. Interpretation: Effective prevention and treatment of child and adolescent OAO is critical to China's health and economic development. Multiple interventions offer a comprehensive approach to address the various factors that increase risk of child and adolescent OAO. Nonetheless, fiscal and regulatory policies offer the strongest health and economic gains. Funding: Funding was provided by UNICEF China.

Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones.

The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2'-bipyridyl/Ag2CO3, whereas the ß-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4'-mono-, 6'-mono- and 4',6'-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1'-position of 13, 3'-position of 14, 4'-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2'-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6'-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.

The case for investing in the prevention and treatment of overweight and obesity among children and adolescents in three middle-income countries.

BACKGROUND: Child and adolescent overweight and obesity rates are increasing rapidly, notably in middle-income countries (MICs). Effective policy adoption has been limited in low-income and middle-income countries. To respond, investment cases were developed in Mexico, Peru, and China to understand the health and economic returns on investment in childhood and adolescent overweight and obesity interventions. METHODS: The investment case model applied a societal perspective to predict the health and economic impact of childhood and adolescent overweight and obesity in a cohort aged 0-19 years, beginning in 2025. Impacts include health-care expenditures, years of life lost, reduced wages, and productivity. Unit cost data from the literature was used to develop a status quo scenario over the model cohort's average expected lifetime period (2025-90 in Mexico; 2025-92 in China and Peru) and was compared with an intervention scenario to estimate cost savings and calculate return on investment (ROI). Effective interventions were identified from the literature and selected to reflect country-specific prioritization after stakeholder discussions. Priority interventions range from fiscal policies, social marketing, breastfeeding promotion, school-based policies, and nutritional counselling. FINDINGS: Total predicted lifetime health and economic impacts of child and adolescent overweight and obesity in the three countries ranged from US$1·8 trillion in Mexico, $211 billion in Peru, and $33 trillion in China. Implementing a set of priority interventions in each country could reduce lifetime costs by $124 billion (Mexico), $14 billion (Peru), and $2 trillion (China). Implementing a unique package of interventions for each country resulted in a predicted lifetime ROI of $515 per $1 invested in Mexico, $164 per $1 in Peru, and $75 per $1 in China. Fiscal policies were very cost-effective and had positive ROIs in all three countries for 30-year, 50-year, and lifetime time horizons until 2090 (Mexico) or 2092 (China and Peru). Although school interventions had a positive ROI in all countries across a lifetime horizon, relatively they yielded considerably lower ROIs than other interventions evaluated. INTERPRETATION: Lifetime health and economic impacts of child and adolescent overweight and obesity across the three MICs are high and will undermine countries' ability to meet sustainable development goals. Investing in nationally relevant cost-effective interventions could reduce lifetime costs. FUNDING: UNICEF, partly supported by a grant from Novo Nordisk.

The effects of Src tyrosine kinase inhibitor, saracatinib, on the markers of epileptogenesis in a mixed-sex cohort of adult rats in the kainic acid model of epilepsy.

Neurodegeneration and neuroinflammation are key processes of epileptogenesis in temporal lobe epilepsy (TLE). A considerable number (∼30%) of patients with epilepsy are resistant to currently available antiseizure drugs and thus there is a need to develop adjunct therapies to modify disease progression. A vast majority of interventional strategies to treat TLE have utilized males which limits the translational nature of the studies. In this study, we investigated the effects of repeated low-dose kainic acid (KA) injection on the initial status epilepticus (SE) and the effects of Src kinase inhibitor, saracatinib (SAR/AZD0530; 20 mg/kg, oral, daily for 7 days), in a mixed-sex cohort of adult Sprague Dawley rats during early epileptogenesis. There were no sex differences in response to KA-induced SE, and neither did the stage of estrus influence SE severity. KA-induced SE caused significant astrogliosis and microgliosis across the hippocampus, piriform cortex, and amygdala. SAR treatment resulted in a significant reduction of microgliosis across brain regions. Microglial morphometrics such as branch length and the endpoints strongly correlated with CD68 expression in the vehicle-treated group but not in the SAR-treated group, indicating mitigation by SAR. KA-induced SE caused significant neuronal loss, including parvalbumin-positive inhibitory neurons, in both vehicle (VEH) and SAR-treated groups. SAR treatment significantly mitigated FJB-positive neuronal counts as compared to the VEH group. There was an increase in C3-positive reactive astrocytes in the VEH-treated group, and SAR treatment significantly reduced the increase in the piriform cortex. C3-positive astrogliosis significantly correlated with CD68 expression in the amygdala (AMY) of VEH-treated rats, and SAR treatment mitigated this relationship. There was a significant increase of pSrc(Y419)-positive microglia in both KA-treated groups with a statistically insignificant reduction by SAR. KA-induced SE caused the development of classical glial scars in the piriform cortex (PIR) in both KA-treated groups, while SAR treatment led to a 42.17% reduction in the size of glial scars. We did not observe sex differences in any of the parameters in this study. SAR, at the dose tested in the rat kainate model for a week in this study mitigated some of the markers of epileptogenesis in both sexes.

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model.

Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops status epilepticus (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration. A total of 1400W is a novel small molecule, which irreversibly inhibits inducible nitric oxide synthase (iNOS) and has been shown to effectively reduce ROS/RNS generation. In this study, we investigated the effects of 1400W treatment for a week or two weeks at 10 mg/kg or 15 mg/kg per day in the rat diisopropylfluorophosphate (DFP) model. 1400W significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the vehicle in different regions of the brain. 1400W also significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum. However, neither of the two concentrations of 1400W for two weeks of treatment had any significant effect on epileptiform spike rate and spontaneous seizures during the treatment period in mixed sex cohorts, males, or females. No significant sex differences were found in response to DFP exposure or 1400W treatment. In conclusion, 1400W treatment at 15 mg/kg per day for two weeks was more effective in significantly reducing DFP-induced nitrooxidative stress, neuroinflammatory and neurodegenerative changes.

Peripheral and central effects of NADPH oxidase inhibitor, mitoapocynin, in a rat model of diisopropylfluorophosphate (DFP) toxicity.

Organophosphates (OP) are highly toxic chemical nerve agents that have been used in chemical warfare. Currently, there are no effective medical countermeasures (MCMs) that mitigate the chronic effects of OP exposure. Oxidative stress is a key mechanism underlying OP-induced cell death and inflammation in the peripheral and central nervous systems and is not mitigated by the available MCMs. NADPH oxidase (NOX) is one of the leading producers of reactive oxygen species (ROS) following status epilepticus (SE). In this study, we tested the efficacy of the mitochondrial-targeted NOX inhibitor, mitoapocynin (MPO) (10 mg/kg, oral), in a rat diisopropylfluorophosphate (DFP) model of OP toxicity. In DFP-exposed animals, MPO decreased oxidative stress markers nitrite, ROS, and GSSG in the serum. Additionally, MPO significantly reduced proinflammatory cytokines IL-1ß, IL-6, and TNF-α post-DFP exposure. There was a significant increase in GP91phox, a NOX2 subunit, in the brains of DFP-exposed animals 1-week post-challenge. However, MPO treatment did not affect NOX2 expression in the brain. Neurodegeneration (NeuN and FJB) and gliosis [microglia (IBA1 and CD68), and astroglia (GFAP and C3)] quantification revealed a significant increase in neurodegeneration and gliosis after DFP-exposure. A marginal reduction in microglial cells and C3 colocalization with GFAP in DFP + MPO was observed. The MPO dosing regimen used in this study at 10 mg/kg did not affect microglial CD68 expression, astroglial count, or neurodegeneration. MPO reduced DFP-induced oxidative stress and inflammation markers in the serum but only marginally mitigated the effects in the brain. Dose optimization studies are required to determine the effective dose of MPO to mitigate DFP-induced changes in the brain.

Sex-based structural and functional MRI outcomes in the rat brain after soman (GD) exposure-induced status epilepticus.

OBJECTIVE: Exposure to the nerve agent, soman (GD), induces status epilepticus (SE), epileptogenesis, and even death. Although rodent models studying the pathophysiological mechanisms show females to be more reactive to soman, no tangible sex differences in brains postexposure have been reported. In this study, we used multimodal imaging using MRI in adult rats to determine potential sex-based biomarkers of soman effects. METHODS: Male and female Sprague Dawley rats were challenged with 1.2 × LD50 soman followed by medical countermeasures. Ten weeks later, the brains were analyzed via structural and functional MRI. RESULTS: Despite no significant sex differences in the initial SE severity after soman exposure, long-term MRI-based structural and functional differences were evident in the brains of both sexes. While T2 MRI showed lesser soman-induced neurodegeneration, large areas of T1 enhancements occurred in females than in males, indicating a distinct pathophysiology unrelated to neurodegeneration. fMRI-based resting-state functional connectivity (RSFC), indicated greater reductions in soman-exposed females than in males, associating with the T1 enhancements (unrelated to neurodegeneration) rather than T2-hyperintensity or T1-hypointensity (representing neurodegeneration). The wider T1 enhancements associating with the decreased spontaneous neuronal activity in multiple resting-state networks in soman-exposed females than males suggest that neural changes unrelated to cellular atrophy impinge on brain function postexposure. Taken together with lower spontaneous neural activity in soman-exposed females, the results indicate some form of neuroprotective state that was not present in males. SIGNIFICANCE: The results indicate that endpoints other than neurodegeneration may need to be considered to translate sex-based nerve agent effects in humans.

The NADPH Oxidase Inhibitor, Mitoapocynin, Mitigates DFP-Induced Reactive Astrogliosis in a Rat Model of Organophosphate Neurotoxicity.

NADPH oxidase (NOX) is a primary mediator of superoxides, which promote oxidative stress, neurodegeneration, and neuroinflammation after diisopropylfluorophosphate (DFP) intoxication. Although orally administered mitoapocynin (MPO, 10 mg/kg), a mitochondrial-targeted NOX inhibitor, reduced oxidative stress and proinflammatory cytokines in the periphery, its efficacy in the brain regions of DFP-exposed rats was limited. In this study, we encapsulated MPO in polyanhydride nanoparticles (NPs) based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and sebacic anhydride (SA) for enhanced drug delivery to the brain and compared with a high oral dose of MPO (30 mg/kg). NOX2 (GP91phox) regulation and microglial (IBA1) morphology were analyzed to determine the efficacy of MPO-NP vs. MPO-oral in an 8-day study in the rat DFP model. Compared to the control, DFP-exposed animals exhibited significant upregulation of NOX2 and a reduced length and number of microglial processes, indicative of reactive microglia. Neither MPO treatment attenuated the DFP effect. Neurodegeneration (FJB+NeuN) was significantly greater in DFP-exposed groups regardless of treatment. Interestingly, neuronal loss in DFP+MPO-treated animals was not significantly different from the control. MPO-oral rescued inhibitory neuronal loss in the CA1 region of the hippocampus. Notably, MPO-NP and MPO-oral significantly reduced astrogliosis (absolute GFAP counts) and reactive gliosis (C3+GFAP). An analysis of inwardly rectifying potassium channels (Kir4.1) in astroglia revealed a significant reduction in the brain regions of the DFP+VEH group, but MPO had no effect. Overall, both NP-encapsulated and orally administered MPO had similar effects. Our findings demonstrate that MPO effectively mitigates DFP-induced reactive astrogliosis in several key brain regions and protects neurons in CA1, which may have long-term beneficial effects on spontaneous seizures and behavioral comorbidities. Long-term telemetry and behavioral studies and a different dosing regimen of MPO are required to understand its therapeutic potential.

Investment case for the prevention and reduction of childhood and adolescent overweight and obesity in Mexico.

Despite efforts to curb the rise in Mexico's child and adolescent overweight and obesity rates, prevalence in Mexico has grown by 120% since 1990 to 43.3% in 2022. This investment case identifies policies that will produce the largest returns for Mexico. The investment case model builds beyond a cost-of-illness analysis by predicting the health and societal economic impact of implementing child and adolescent overweight and obesity interventions in a cohort aged 0-19 from 2025 to 2090. The Markov model's impacts include healthcare expenditures, years of life lost, and reduced wages and productivity. We projected and compared costs in a status quo scenario to an intervention scenario to estimate cost savings and calculate return-on-investment (ROI). Total lifetime health and economic costs amount to USD 1.8 trillion-USD 30 billion on average per year. Implementing five interventions can reduce lifetime costs by approximately 7%. Each intervention has a low cost per disability-adjusted life year averted over 30-year, 50-year, and lifetime horizons. The findings demonstrate that a package of interventions mitigating child and adolescent overweight and obesity offers a strong ROI. The novel investment case methods should be applied to other countries, particularly low- and middle-income countries.

Disease-Modifying Effects of a Glial-targeted Inducible Nitric Oxide Synthase Inhibitor (1400W) in Mixed-sex Cohorts of a Rat Soman (GD) Model of Epilepsy.

Background Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs- atropine, oximes, benzodiazepines), if administered in < 20 minutes of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for three days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure. Methods Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132µg/kg, s.c.) and immediately treated with atropine (2mg/kg, i.m) and HI-6 (125mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3mg/kg, i.m.). An hour post-midazolam, 1400W (20mg/kg, i.m.) or vehicle was administered daily for two weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays. Results We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68 positive glia) as a measure of neuroinflammation, and neurodegeneration (including parvalbumin positive neurons) in some brain regions. Conclusion These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration, and neuronal hyperexcitability.

Inhibition of LILRB2 by a Novel Blocking Antibody Designed to Reprogram Immunosuppressive Macrophages to Drive T-Cell Activation in Tumors.

Tumor-associated macrophages (TAM) play an important role in maintaining the immunosuppressive state of the tumor microenvironment (TME). High levels of CD163+ TAMs specifically are associated with poor prognosis in many solid tumor types. Targeting TAMs may represent a key approach in development of the next generation of cancer immune therapeutics. Members of the leukocyte immunoglobulin-like receptor B (LILRB) family, including LILRB2 (ILT4), are known to transmit inhibitory signals in macrophages and other myeloid cells. Leveraging bulk and single cell RNA-sequencing datasets, as well as extensive immunophenotyping of human tumors, we found that LILRB2 is highly expressed on CD163+ CD11b+ cells in the TME and that LILRB2 expression correlates with CD163 expression across many tumor types. To target LILRB2, we have developed JTX-8064, a highly potent and selective antagonistic mAb. JTX-8064 blocks LILRB2 binding to its cognate ligands, including classical and nonclassical MHC molecules. In vitro, JTX-8064 drives the polarization of human macrophages and dendritic cells toward an immunostimulatory phenotype. As a result, human macrophages treated with a LILRB2 blocker are reprogrammed to increase the activation of autologous T cells in co-culture systems. Furthermore, JTX-8064 significantly potentiates the activity of anti-PD-1 in allogeneic mixed lymphocyte reaction. In a human tumor explant culture, pharmacodynamic activity of JTX-8064 was observed in monotherapy and in combination with anti-PD-1. Collectively, our work provides strong translational and preclinical rationale to target LILRB2 in cancer.

Rate of change in early Huntington's disease: a clinicometric analysis.

Sensitive outcome measures for patients with Huntington's disease (HD) are required for future clinical trials. Longitudinal data were collected from a 3-year study of 379 patients suffering from early HD who were not treated by antipsychotics. Progression of UHDRS item scores was evaluated by linear regression and slope, whereas correlation coefficient, standard error, and P values were estimated on the basis of the data of eight evaluations from screening to study end (36 months). For the functional assessment dimension, the proportion of "no" responses at baseline and at study end was determined. Linear progression was observed for the motor score and for all three functional measures (i.e., functional assessment score, independence assessment score, and total functional capacity score). In contrast, there was little evidence for progression of the behavioral assessment score over the study period, whereas the cognitive assessment score was intermediate. Twenty-two motor-score items showed linear progression, with a slope of >0.003. These included all chorea items, finger tapping and pronation/supination (left and right), gait, tongue protrusion, and tandem walking. Different symptom domains and individual items evolved at different rates in this group of patients suffering from early HD. It may be possible to select sensitive items to create a simplified version of the UHDRS, which would be more efficient and more sensitive for the assessment of disease progression in clinical trials and natural history studies.

Perceptions on a mobile health intervention to improve maternal child health for Syrian refugees in Turkey: Opportunities and challenges for end-user acceptability.

Background: Mobile health (mhealth) technology presents an opportunity to address many unique challenges refugee populations face when accessing healthcare. A robust body of evidence supports the use of mobile phone-based reminder platforms to increase timely and comprehensive access to health services. Yet, there is a dearth of research in their development for displaced populations, as well as refugee perspectives in design processes to improve effective adoptions of mhealth interventions. Objective: This study aimed to explore healthcare barriers faced by Syrian refugee women in Turkey, and their perceptions of a maternal-child health mobile application designed to provide antenatal care and vaccine services. These findings guided development of a framework for enhancing acceptability of mobile health applications specific to refugee end-users. Methods: Syrian refugee women who were pregnant or had at least one child under the age of 2 years old at the time of recruitment (n = 14) participated in semi-structured in-depth interviews. Participants had the opportunity to directly interact with an operational maternal-child health mobile application during the interview. Using a grounded theory approach, we identified critical factors and qualities mhealth developers should consider when developing user-friendly applications for refugees. Results: It was observed that a refugee's perception of the mobile health application's usability was heavily influenced by past healthcare experiences and the contextual challenges they face while accessing healthcare. The in-depth interviews with refugee end-users identified that data security, offline capability, clear-user directions, and data retrievability were critical qualities to build into mobile health applications. Among the features included in the maternal-child health application, participants most valued the childhood vaccination reminder and health information features. Furthermore, the application's multi-lingual modes (Arabic, Turkish, and English) strengthened the application's usability among Syrian refugee populations living in Turkey. Conclusions: The inclusion of refugee perceptions in mhealth applications offers unique developer insights for building more inclusive and effective tools for vulnerable populations. Basic upfront discussions of the mobile application's health goals and its personal value to the user may improve their long-term use. Further prospective research is needed on retention and use of mobile health applications for refugee women and other displaced populations.