Common and varied molecular responses of Escherichia coli to five different inhibitors of the lipopolysaccharide biosynthetic enzyme LpxC.

A promising yet clinically unexploited antibiotic target in difficult-to-treat Gram-negative bacteria is LpxC, the key enzyme in the biosynthesis of lipopolysaccharides, which are the major constituents of the outer membrane. Despite the development of dozens of chemically diverse LpxC inhibitor molecules, it is essentially unknown how bacteria counteract LpxC inhibition. Our study provides comprehensive insights into the response against five different LpxC inhibitors. All compounds bound to purified LpxC from Escherichia coli. Treatment of E. coli with these compounds changed the cell shape and stabilized LpxC suggesting that FtsH-mediated proteolysis of the inactivated enzyme is impaired. LpxC inhibition sensitized E. coli to vancomycin and rifampin, which poorly cross the outer membrane of intact cells. Four of the five compounds led to an accumulation of lyso-phosphatidylethanolamine, a cleavage product of phosphatidylethanolamine, generated by the phospholipase PldA. The combined results suggested an imbalance in lipopolysaccharides and phospholipid biosynthesis, which was corroborated by the global proteome response to treatment with the LpxC inhibitors. Apart from LpxC itself, FabA and FabB responsible for the biosynthesis of unsaturated fatty acids were consistently induced. Upregulated compound-specific proteins are involved in various functional categories, such as stress reactions, nucleotide, or amino acid metabolism and quorum sensing. Our work shows that antibiotics targeting the same enzyme do not necessarily elicit identical cellular responses. Moreover, we find that the response of E. coli to LpxC inhibition is distinct from the previously reported response in Pseudomonas aeruginosa.

Multimodal Assessment of Emotion Dysregulation in Children with and without ADHD and Disruptive Behavior Disorders.

OBJECTIVE: We sought to explore if specific domains of emotion dysregulation (emotion regulation [EREG], emotional reactivity/lability [EREL], emotion recognition/understanding [ERU], and callous-unemotional [CU] behaviors) were uniquely associated with diagnostic classifications. METHOD: This study utilized a multimodal (parent/teacher [P/T] reports and behavioral observations) approach to examine emotion dysregulation in a sample of young children (68.7% boys; mean age = 5.47, SD = 0.77, 81.4% Latinx) with attention-deficit/hyperactivity disorder (ADHD Only; n = 46), ADHD + disruptive behavior disorders (ADHD+DBD; n = 129), and typically developing (TD) children (n = 148). RESULTS: All three diagnostic groups were significantly different from one another on P/T reports of EREG, EREL and CU. For the ADHD+DBD group, P/T reported worse EREG and EREL, and higher mean scores of CU, compared to both ADHD Only and TD groups. The ADHD+DBD group also performed significantly worse than the TD group (but not the ADHD Only group) on observed measures of EREG, EREL and ERU. P/T reported EREG, EREL and CU for the ADHD Only group were significantly worse than the TD group. Using multinomial logistic regression, P/T reported EREG, EREL, and CU were significantly associated with diagnostic status above and beyond observed measures of emotion dysregulation. The model successfully classified children with ADHD+DBD (91.3%) and TD (95.9%); however, children in the ADHD Only group were correctly identified only 45.7% of time. CONCLUSION: Our findings suggest that measures of emotion dysregulation may be particularly helpful in correctly identifying children with ADHD+DBD, but not necessarily children with ADHD Only.

Physiology of trans-translation deficiency in Bacillus subtilis - a comparative proteomics study.

trans-Translation is the most effective ribosome rescue system known in bacteria. While it is essential in some bacteria, Bacillus subtilis possesses two additional alternative ribosome rescue mechanisms that require the proteins BrfA or RqcH. To investigate the physiology of trans-translation deficiency in the model organism B. subtilis, we compared the proteomes of B. subtilis 168 and a ΔssrA mutant in the mid-log phase using gel-free label-free quantitative proteomics. In chemically defined medium, the growth rate of the ssrA deletion mutant was 20% lower than that of B. subtilis 168. An 35 S-methionine incorporation assay demonstrated that protein synthesis rates were also lower in the ΔssrA strain. Alternative rescue factors were not detected. Among the 34 proteins overrepresented in the mutant strain were eight chemotaxis proteins. Indeed, both on LB agar and minimal medium the ΔssrA strain showed an altered motility and chemotaxis phenotype. Despite the lower growth rate, in the mutant proteome ribosomal proteins were more abundant while proteins related to amino acid biosynthesis were less abundant than in the parental strain. This overrepresentation of ribosomal proteins coupled with a lower protein synthesis rate and down-regulation of precursor supply reflects the slow ribosome recycling in the trans-translation-deficient mutant.

Effects of 4-Br-A23187 on Bacillus subtilis cells and unilamellar vesicles reveal it to be a potent copper ionophore.

Ionophores are small molecules or peptides that transport metal ions across biological membranes. Their transport capabilities are typically characterized in vitro using vesicles and single ion species. It is difficult to infer from these data which effects ionophores have on living cells in a complex environment (e.g., culture medium), since net ion movement is influenced by many factors including ion composition of the medium, concentration gradients, pH gradient, and protein-mediated transport processes across the membrane. To gain insights into the antibacterial mechanism of action of the semisynthetic polyether ionophore 4-Br-A23187, known to efficiently transport zinc and manganese in vitro, we investigated its effects on the gram-positive model organism Bacillus subtilis. In addition to monitoring cellular ion concentrations, the physiological impact of treatment was assessed on the proteome level. 4-Br-A23187 treatment resulted in an increase in intracellular copper levels, the extent of which depended on the copper concentration of the medium. Effects of copper accumulation mirrored by the proteomic response included oxidative stress, disturbance of proteostasis, metal and sulfur homeostasis. The antibiotic effect of 4-Br-A23187 is further aggravated by a decrease in intracellular manganese and magnesium. A liposome model confirmed that 4-Br-A23187 acts as copper ionophore in vitro.

Analgesic effect of recombinant GABAergic precursors releasing ω-conotoxin MVIIA in a model of peripheral nerve injury in rats.

Development of chronic pain has been attributed to dysfunctional GABA signaling in the spinal cord. Direct pharmacological interventions on GABA signaling are usually not very efficient and often accompanied by side effects due to the widespread distribution of GABA receptors in CNS. Transplantation of GABAergic neuronal cells may restore the inhibitory potential in the spinal cord. Grafted cells may also release additional analgesic peptides by means of genetic engineering to further enhance the benefits of this approach. Conopeptides are ideal candidates for recombinant expression using cell-based strategies. The omega-conopeptide MVIIA is in clinical use for severe pain marketed as FDA approved Prialt in the form of intrathecal injections. The goal of this study was to develop transplantable recombinant GABAergic cells releasing conopeptide MVIIA and to evaluate the analgesic effect of the grafts in a model of peripheral nerve injury-induced pain. We have engineered and characterized the GABAergic progenitors expressing MVIIA. Recombinant and nonrecombinant cells were intraspinally injected into animals after the nerve injury. Animals were tested weekly up to 12 weeks for the presence of hypersensitivity, followed by histochemical and biochemical analysis of the tissue. We observed beneficial effects of the grafted cells in reducing hypersensitivity in all grafted animals, especially potent in the recombinant group. The level of pain-related cytokines was reduced in the grafted animals and correlation between these pain markers and actual behavior was indicated. This study demonstrated the feasibility of recombinant cell transplantation in the management of chronic pain.

Structural and diffusion-weighted brain imaging predictors of attention-deficit/hyperactivity disorder and its symptomology in very young (4- to 7-year-old) children.

The current study aimed to identify the key neurobiology of attention-deficit/hyperactivity disorder (ADHD), as it relates to ADHD diagnostic category and symptoms of hyperactive/impulsive behaviour and inattention. To do so, we adapted a predictive modelling approach to identify the key structural and diffusion-weighted brain imaging measures and their relative standing with respect to teacher ratings of executive function (EF) (measured by the Metacognition Index of the Behavior Rating Inventory of Executive Function [BRIEF]) and negativity and emotion regulation (ER) (measured by the Emotion Regulation Checklist [ERC]), in a critical young age range (ages 4 to 7, mean age 5.52 years, 82.2% Hispanic/Latino), where initial contact with educators and clinicians typically take place. Teacher ratings of EF and ER were predictive of both ADHD diagnostic category and symptoms of hyperactive/impulsive behaviour and inattention. Among the neural measures evaluated, the current study identified the critical importance of the largely understudied diffusion-weighted imaging measures for the underlying neurobiology of ADHD and its associated symptomology. Specifically, our analyses implicated the inferior frontal gyrus as a critical predictor of ADHD diagnostic category and its associated symptomology, above and beyond teacher ratings of EF and ER. Collectively, the current set of findings have implications for theories of ADHD, the relative utility of neurobiological measures with respect to teacher ratings of EF and ER, and the developmental trajectory of its underlying neurobiology.

Individual Differences in Germ Spreading Behaviors Among Children With Attention-Deficit/Hyperactivity Disorder: The Role of Executive Functioning.

OBJECTIVE: Infectious diseases, such as coronavirus disease 2019 (COVID-19), are commonly transmitted by respiratory droplets and contact with contaminated surfaces. Individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to be infected with COVID-19 and experience more hospitalizations than individuals without ADHD. The current study investigated the role of ADHD symptomatology and executive functioning (EF) in germ spreading behavior frequency among young children with and without ADHD and parenting responses to these behaviors. METHODS: Participants included 53 children diagnosed with ADHD and 47 typically developing (TD) children between the ages of 4-5 years (76% male; Mage = 4.62; 86% Hispanic/Latinx). Parents and teachers reported on children's ADHD symptomatology and children completed three EF tasks. Germ spreading behavior frequency (direct contact of hand to face and toy in mouth) and parenting responses (verbal and nonverbal behaviors) were observed during a 5-min parent-child play situation. RESULTS: Negative binomial regression analyses indicated that both ADHD diagnostic status and poor metacognition predicted both higher rates of toy to mouth (ß = 1.94, p < .001; ß = 0.03, p = .004) and face touching frequency (ß = 0.60, p = .03; ß = 0.03, p = .004), respectively. Additionally, poor attention and worse cognitive flexibility only predicted higher rates of toy to mouth frequency (ß = 0.09, p < .001; ß = -0.04, p = .001), respectively. CONCLUSIONS: Young children with ADHD are at high risk for spreading germs via putting toys in their mouth and touching their face. Particularly, high levels of inattention and poor EF appear to be associated with higher rates of germ spreading behaviors.

Manufacturing considerations for producing and assessing decellularized extracellular matrix hydrogels.

Although several decellularized extracellular matrix (ECM) sheets or patches have been commercialized for use in the clinic, only one injectable decellularized ECM hydrogel, a decellularized myocardial matrix, has reached clinical trials. Consequently, very little information is available for established manufacturing standards or assessments of these materials. Here we present detailed methodology for investigating three parameters related to manufacturing optimization for a porcine derived skeletal muscle ECM hydrogel - animal-to-animal variability, bioburden reduction, and harvesting conditions. Results from characterization assays, including residual dsDNA content and sulfated glycosaminoglycan content, did not yield noteworthy differences amongst individual animals or following the addition of a bioburden reducing agent. However, the tissue collected under different harvesting conditions contained varying amounts of fat, and the protein compositions of the decellularized products differed, which could ultimately impact subsequent efficacy in vitro or in vivo. As decellularized ECM hydrogels continue to be evaluated for various applications, the differences between laboratory-scale and manufacturing-scale material batches should be thoroughly considered to avoid costly and timely optimization during scale-up.

Evolutionary genomics and biosynthetic potential of novel environmental Actinobacteria.

Actinobacteria embroil Gram-positive microbes with high guanine and cytosine contents in their DNA. They are the source of most antimicrobials of bacterial origin utilized in medicine today. Their genomes are among the richest in novel secondary metabolites with high biotechnological potential. Actinobacteria reveal complex patterns of evolution, responses, and adaptations to their environment, which are not yet well understood. We analyzed three novel plant isolates and explored their habitat adaptation, evolutionary patterns, and potential secondary metabolite production. The phylogenomically characterized isolates belonged to Actinoplanes sp. TFC3, Streptomyces sp. L06, and Embleya sp. NF3. Positively selected genes, relevant in strain evolution, encoded enzymes for stress resistance in all strains, including porphyrin, chlorophyll, and ubiquinone biosynthesis in Embleya sp. NF3. Streptomyces sp. L06 encoded for pantothenate and proteins for CoA biosynthesis with evidence of positive selection; furthermore, Actinoplanes sp. TFC3 encoded for a c-di-GMP synthetase, with adaptive mutations. Notably, the genomes harbored many genes involved in the biosynthesis of at least ten novel secondary metabolites, with many avenues for future new bioactive compound characterization-specifically, Streptomyces sp. L06 could make new ribosomally synthesized and post-translationally modified peptides, while Embleya sp. NF3 could produce new non-ribosomal peptide synthetases and ribosomally synthesized and post-translationally modified peptides. At the same time, TFC3 has particularly enriched in terpene and polyketide synthases. All the strains harbored conserved genes in response to diverse environmental stresses, plant growth promotion factors, and degradation of various carbohydrates, which supported their endophytic lifestyle and showed their capacity to colonize other niches. This study aims to provide a comprehensive estimation of the genomic features of novel Actinobacteria. It sets the groundwork for future research into experimental tests with new bioactive metabolites with potential application in medicine, biofertilizers, and plant biomass residue utilization, with potential application in medicine, as biofertilizers and in plant biomass residues utilization. KEY POINTS: • Potential of novel environmental bacteria for secondary metabolites production • Exploring the genomes of three novel endophytes isolated from a medicinal tree • Pan-genome analysis of Actinobacteria genera.

Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation.

New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.

A CuAAC Click Approach for the Introduction of Bidentate Metal Complexes to a Sulfanilamide-Derived Antibiotic Fragment.

A simple "click-chemistry" approach was employed in order to functionalize the known antibiotic fragment sulfanilamide with a bidentate pyridyl-triazole pocket, which allowed for the synthesis of ruthenium(II) and rhenium(I) carbonyl chloride complexes. Six new complexes were prepared and comprehensively characterized, including five single crystal X-ray structures, photophysical characterization, and testing for antimicrobial activity. Interestingly, functionalization of the pyridine ring with an ortho-hydroxymethyl group resulted in a greater than 100-fold increase in the rate of ligand release in a dimethylsulfoxide solution. Subsequent studies indicated this process could be further accelerated by irradiation with 265 nm light. Structural characterization of four of the complexes indicates that this is the result of a lengthening and weakening of the Re-NPyridine bond (average (Ltri) = 2.19 Å vs LtriOH = 2.25 Å) due to the steric influence of the hydroxymethyl group. The organometallic rhenium(I) pyridyl-triazole functionality maintains its characteristic fluorescent properties despite the presence of the sulfonamide moiety. Two of the compounds showed modest antimicrobial activity against methicillin-resistant Staphylococcus aureus, whereas the structurally similar sulfamethoxazole alone showed no activity under the same conditions.

The plant-derived chalcone Xanthoangelol targets the membrane of Gram-positive bacteria.

Xanthoangelol is a geranylated chalcone isolated from fruits of Amorpha fructicosa that exhibits antibacterial effects at low micromolar concentration against Gram-positive bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Enterococcus faecalis. We demonstrate that Xanthoangelol treatment of Gram-positive bacteria affects bacterial membrane integrity and leads to a leakage of intracellular metabolites. This correlates with a rapid collapse of the membrane potential and results in a fast and strong bactericidal effect. Proteomic profiling of Xanthoangelol-treated cells revealed signatures of cell wall and/or membrane damage and oxidative stress. Xanthoangelol specifically disturbs the membrane of Gram-positive bacteria potentially by forming pores resulting in cell lysis. In contrast, Xanthoangelol treatment of human cells showed only mildly hemolytic and cytotoxic effects at higher concentrations. Therefore, geranylated chalcones such as Xanthoangelol are promising lead structures for new antimicrobials against drug-resistant gram-positive pathogens.

Carbon catabolite regulation in Streptomyces: new insights and lessons learned.

One of the most significant control mechanisms of the physiological processes in the genus Streptomyces is carbon catabolite repression (CCR). This mechanism controls the expression of genes involved in the uptake and utilization of alternative carbon sources in Streptomyces and is mostly independent of the phosphoenolpyruvate phosphotransferase system (PTS). CCR also affects morphological differentiation and the synthesis of secondary metabolites, although not all secondary metabolite genes are equally sensitive to the control by the carbon source. Even when the outcome effect of CCR in bacteria is the same, their essential mechanisms can be rather different. Although usually, glucose elicits this phenomenon, other rapidly metabolized carbon sources can also cause CCR. Multiple efforts have been put through to the understanding of the mechanism of CCR in this genus. However, a reasonable mechanism to explain the nature of this process in Streptomyces does not yet exist. Several examples of primary and secondary metabolites subject to CCR will be examined in this review. Additionally, recent advances in the metabolites and protein factors involved in the Streptomyces CCR, as well as their mechanisms will be described and discussed in this review.

Effects of landscape, resource use, and body size on genetic structure in bee populations.

Quantifying genetic structure and levels of genetic variation are fundamentally important to predicting the ability of populations to persist in human-altered landscapes and adapt to future environmental changes. Genetic structure reflects the dispersal of individuals over generations, which can be mediated by species-level traits or environmental factors. Dispersal distances are commonly positively associated with body size and negatively associated with the amount of degraded habitat between sites, motivating the investigation of these potential drivers of dispersal concomitantly. We quantified genetic structure and genetic variability within populations of seven bee species from the genus Euglossa across fragmented landscapes. We genotyped bees at SNP loci and tested the following predictions: (1) deforested areas restrict gene flow; (2) larger species have lower genetic structure; (3) species with greater resource specialization have higher genetic structure; and (4) sites surrounded by more intact habitat have higher genetic diversity. Contrasting with previous work on bees, we found no associations between body size and genetic structure. Genetic structure was higher for species with greater resource specialization, and the amount of intact habitat between or surrounding sites was positively associated with parameters reflecting gene flow and genetic diversity. These results challenge the dominant paradigm that individuals of larger species disperse farther, and they suggest that landscape and resource requirements are important factors mediating dispersal.

A Systematic Review of Infant Mental Health Prevention and Treatment Programs.

Although many prevention and treatment programs exist for children and families, there have been no reviews specifically examining their impact on infant mental health at the program level. Therefore, the purpose of the current review was to a) systematically examine prevention and treatment programs targeting infant mental health outcomes (i.e., internalizing problems, externalizing problems, social-emotional development, trauma) or the parent-infant relationship/ attachment in children from pregnancy to 2 years; b) classify each program by level of empirical support; and c) highlight strengths and identify gaps in the existing literature to inform future mental health intervention science. From over 121,341 publications initially identified, 60 prevention and treatment programs met inclusion criteria for this review. Each program was reviewed for level of scientific evidence. Of the 60 programs reviewed, 29 (48.33%) were classified as promising, while only six (10.0%) were classified as effective. Lastly, only two programs (3.33%; Attachment and Biobehavioral Catch-Up and Video-feedback Intervention Parenting Program) were classified as evidence-based specific to infant mental health and/or parent-infant relationship/attachment outcomes. Implications related to disseminating evidence-based prevention/treatment programs are discussed.

Mental health prevention and treatment programs for infants experiencing homelessness: A systematic review.

Experiencing homelessness in infancy has been linked to negative physical and mental health outcomes. Parental well-being and the parent-infant relationship can also be negatively impacted by experiencing homelessness. While numerous parent-based infant mental health programs have been identified by a recent review, the goal of this study was to further determine the extent to which these existing programs were developed and/or examined with at-risk populations such as families experiencing homelessness. Out of 60 programs identified by Hare et al., in press, only three had been implemented specifically in shelter settings with infants 0-12 months (Parent-Infant Psychotherapy, New Beginnings, and My Baby's First Teacher). Additionally, when examining programs that began in later infancy (after 12 months), only 2 programs were implemented in shelter settings (Incredible Years and Parent-Child Interaction Therapy). Implications for research, policy, and clinicians regarding implementation of evidence-based prevention/treatment programs for parents and their infants experiencing homelessness are discussed.

Reduced recruitment of inhibitory control regions in very young children with ADHD during a modified Kiddie Continuous Performance Task: a fMRI study.

Attention-Deficit/Hyperactivity Disorder (ADHD) symptom profiles are known to undergo changes throughout development, rendering the neurobiological assessment of ADHD challenging across different developmental stages. Particularly in young children (ages 4 to 7 years), measuring inhibitory control network activity in the brain has been a formidable task due to the lack of child-friendly functional Magnetic Resonance Imaging (fMRI) paradigms. This study aims to address these difficulties by focusing on measuring inhibitory control in very young children within the MRI environment. A total of 56 children diagnosed with ADHD and 78 typically developing (TD) 4-7-year-old children were examined using a modified version of the Kiddie-Continuous Performance Test (K-CPT) during BOLD fMRI to assess inhibitory control. We concurrently evaluated their performance on the established and standardized K-CPT outside the MRI scanner. Our findings suggest that the modified K-CPT effectively elicited robust and expected brain activity related to inhibitory control in both groups. Comparisons between the two groups revealed subtle differences in brain activity, primarily observed in regions associated with inhibitory control, such as the inferior frontal gyrus, anterior insula, dorsal striatum, medial pre-supplementary motor area (pre-SMA), and cingulate cortex. Notably, increased activity in the right anterior insula was associated with improved response time (RT) and reduced RT variability on the K-CPT administered outside the MRI environment, although this did not survive statistical correction for multiple comparisons. In conclusion, our study successfully overcame the challenges of measuring inhibitory control in very young children within the MRI environment by utilizing a modified K-CPT during BOLD fMRI. These findings shed light on the neurobiological correlates of inhibitory control in ADHD and TD children, provide valuable insights for understanding ADHD across development, and potentially inform ADHD diagnosis and intervention strategies. The research also highlights remaining challenges with task fMRI in very young clinical samples.

Navigating Treatment Challenges: A Case Study on Refractory Psychosis in a Chronic MDMA (3,4-Methylenedioxymethamphetamine) User.

MDMA (3,4-methylenedioxy​methamphetamine), also known as Ecstasy, is a synthetic amphetamine with hallucinogenic and stimulant properties, which has become increasingly favored as a substance for recreational use. Despite its deceptive reputation as "safe," chronic MDMA use is associated with neuropsychiatric complications, including psychosis. We describe a case of a 23-year-old woman with chronic MDMA use disorder and childhood trauma, who presented with severe psychosis and catatonic features. While initial diagnostic possibilities included drug-induced psychosis and mood disorders, the patient's history and presentation supported a diagnosis of bipolar I disorder with psychotic features, which was exacerbated by MDMA use. Conventional antipsychotics failed to improve psychotic symptoms and led to worsening of catatonia, requiring electroconvulsive therapy (ECT) for improvement. Socioeconomic barriers hindered follow-up care, leading to an Emergency Department (ED) admission shortly after discharge. This case highlights the intricate interplay between substance use, psychiatric illness, and trauma, and showcases ECT's efficacy in severe psychosis. It emphasizes the necessity for comprehensive mental health services, especially for vulnerable populations, and calls for further research into MDMA's psychiatric effects and optimal treatment approaches for individuals with co-occurring substance use and psychiatric disorders.

Markedly Delayed Presentation of a Psychotic Disorder 10 Years After the First Onset of Symptoms.

Schizophrenia affects 1% of the population, causing chronic debilitating symptoms with largely unknown causes. Structural brain changes and neurochemical alterations are believed to contribute to its etiology. Delayed treatment initiation is a major concern. This case involves a male patient with a decade-long history of psychosis, experiencing isolation, agoraphobia, and paranoid delusions. His situation deteriorated to the point where he lived in a self-imposed physically constraining environment for a year, leading to muscle atrophy and deteriorating health. Delayed help-seeking was driven by insurance concerns, despite prior academic success. Following extensive evaluation, he received the diagnosis of schizophrenia (first episode, severe), requiring multidisciplinary treatment, including medication adjustments and therapy. This case serves as a poignant illustration of a missed opportunity for early intervention, with treatment initiated only after symptoms became severe. Research indicates that early intervention in schizophrenia is crucial, typically leading to improved outcomes, emphasizing its critical importance.

Community-Delivered Evidence-Based Practice and Usual Care for Adolescent Attention-Deficit/Hyperactivity Disorder: Examining Mechanistic Outcomes.

Previous research suggests that routine psychosocial care for adolescents with attention-deficit/hyperactivity disorder (ADHD) is an eclectic and individualized mix of diluted evidence-based practices (EBPs) and low-value approaches. This study evaluated the extent to which a community-delivered EBP and usual care (UC) for adolescents with ADHD produce differential changes in theorized behavioral, psychological, and cognitive mechanisms of ADHD. A randomized community-based trial was conducted with double randomization of adolescent and community therapists to EBP delivery supports (Supporting Teens' Autonomy Daily [STAND]) versus UC delivery. Participants were 278 culturally diverse adolescents (ages 11-17) with ADHD and caregivers. Mechanistic outcomes were measured at baseline, post-treatment, and follow-up using parent-rated, observational, and task-based measures. Results using linear mixed models indicated that UC demonstrated superior effects on parent-rated and task-based executive functioning relative to STAND. However, STAND demonstrated superior effects on adolescent motivation and reducing parental intrusiveness relative to UC when it was delivered by licensed therapists. Mechanisms of community-delivered STAND and UC appear to differ. UC potency may occur through improved executive functioning, whereas STAND potency may occur through improved teen motivation and reducing low-value parenting practices. However, when delivered by unlicensed, community-based therapists, STAND did not enact proposed mechanisms. Future adaptations of community-delivered EBPs for ADHD should increase supports for unlicensed therapists, who comprise the majority of the community mental health workforce.